@article {pmid41803285,
year = {2026},
author = {Kalecký, K and Buitrago, L and Alarcon, JM and Singh, A and Bottiglieri, T and Kaddurah-Daouk, R and Hernández, AI},
title = {Fingolimod normalizes metabolic signatures associated with synaptic plasticity and memory in APP/PS1 model: Sphingosine-1-phosphate receptor a therapeutic target for Alzheimer's.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41803285},
issn = {2045-2322},
support = {U01AG061359; U19AG063744; 3U19AG063744-04S1; R01AG046171; RF1AG059093; RF1AG058942; RF1AG051550/NH/NIH HHS/United States ; U01AG061359; U19AG063744; 3U19AG063744-04S1; R01AG046171; RF1AG059093; RF1AG058942; RF1AG051550/NH/NIH HHS/United States ; },
abstract = {UNLABELLED: Previously, our metabolomic, transcriptomic, and genomic studies characterized the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer’s disease, and we demonstrated that FTY720, a sphingosine-1-phospahate receptor modulator approved for treatment of multiple sclerosis, recovers synaptic plasticity and memory in APP/PS1 mice. To further investigate how FTY720 rescues the pathology, we performed metabolomic analysis in brain, plasma, and liver of trained APP/PS1 and wild-type mice. APP/PS1 mice showed area-specific brain disturbances in polyamines, phospholipids, and sphingolipids. Most changes were completely or partially normalized in FTY720-treated subjects, indicating rebalancing the “sphingolipid rheostat”, possibly reactivating phosphatidylethanolamine synthesis via mitochondrial phosphatidylserine decarboxylase pathway, and normalizing polyamine levels that are known to support mitochondrial activity. Synaptic plasticity and memory were rescued, with spermidine synthesis in temporal cortex best corresponding to hippocampal CA3-CA1 plasticity normalization. FTY720 effects, also reflected in other pathways, are consistent with promotion of mitochondrial function, synaptic plasticity, and anti-inflammatory environment, while reducing pro-apoptotic and pro-inflammatory signals. Additional mechanistic studies should validate the contribution of the suggested pathways to the treatment effects.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-42518-8.},
}

@article {pmid42013744,
year = {2026},
author = {Zhao, X and Bao, Y and Wan, X and Miao, R and Li, C and Wang, J and Zhang, H and Xiang, Y and Pang, Y and Miao, Z and Tong, M and Shi, X and Wang, H and Gong, P and Zhao, Y and Hou, Y},
title = {Design, synthesis, and evaluation of dual-target inhibitors of acetylcholinesterase (AChE) and soluble epoxide hydrolase (sEH) for the treatment of Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {312},
number = {},
pages = {118844},
doi = {10.1016/j.ejmech.2026.118844},
pmid = {42013744},
issn = {1768-3254},
abstract = {In this study, a series of tacrine derivatives featuring a triazole linker with sEH fragment were designed, synthesized, and evaluated for Alzheimer's disease treatment. Among them, compound Z43 exhibited best dual inhibitory activity against AChE and sEH (AChE IC50 = 1.7 nM; sEH IC50 = 0.7 nM) and showed low cytotoxicity in HepG2, SMMC7721 and SH-SY5Y cell lines. In addition, Z43 showed high permeability in PAMPA permeability test. Meanwhile, Z43 protected PC12 cells from H2O2-induced toxicity. Moreover, in LPS-induced BV-2 cell inflammation model, Z43 significantly reduced the levels of TNF-α, IL-1β, IL-6 and iNOS. Acute toxicity tests also indicated a favorable safety profile. In the scopolamine-induced AD mice model, Z43 markedly improved learning and memory deficits, which was significantly better than tacrine and EC5026. In summary, compound Z43 shows promising potential for further research.},
}

@article {pmid42014236,
year = {2026},
author = {Corcoran, E and Kettlety, M and Mogul, U and Azah, JN and Cork, SC},
title = {The effects of GLP-1 receptor agonists on Alzheimer's pathophysiology: A systematic review.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104091},
doi = {10.1016/j.mcn.2026.104091},
pmid = {42014236},
issn = {1095-9327},
abstract = {BACKGROUND: The incidence of Alzheimer's disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in AD. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of liraglutide, semaglutide, exenatide and dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and Aβ.

METHODS: A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified.

RESULTS: This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer's disease pathology, particularly Aβ plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models while also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. An EXSCEL trial showed significant changes in systemic inflammatory markers. While pre-clinical data has been encouraging, clinical evidence remains limited.

CONCLUSIONS: There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ levels and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings have so far failed to demonstrate an arresting effect on cognitive.

REGISTRATION: PROSPERO CRD420251029748.},
}

@article {pmid42014786,
year = {2026},
author = {Kim, OH and Shin, CH and Cho, MW and Ha, JY and Choung, JJ and Song, DK and Choi, JY and Chang, ES and Lee, HJ and Ku, SK},
title = {Transcranial vibrotactile stimulation enhances hippocampal cholinergic signaling and memory through frequency-dependent mechanotransduction.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49377-3},
pmid = {42014786},
issn = {2045-2322},
abstract = {Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline.},
}

@article {pmid42015253,
year = {2026},
author = {Reetz, K and Liepelt-Scarfone, I and Häger, A and Flöel, A and Schulz, JB and , },
title = {The best treatment is prevention: prevention of cognitive decline and dementia - current state, gaps and next steps.},
journal = {Neurological research and practice},
volume = {8},
number = {1},
pages = {},
pmid = {42015253},
issn = {2524-3489},
}

@article {pmid42015299,
year = {2026},
author = {Ge, C and Wang, K and Tang, H and Ke, Y and Wang, H and Fu, Q and Xiu, Y and Guo, Y and Jia, YF and Long, Z and He, G and Tang, Q},
title = {NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42015299},
issn = {2047-9158},
support = {BJRC202310//Project of the Top-Notch Talent Cultivation Program for the Graduate Students of Chongqing Medical University/ ; W0168//Program for Youth Innovation in Future Medicine, Chongqing Medical University/ ; 82371203//National Natural Science Foundation of China/ ; 82201582//National Natural Science Foundation of China/ ; CSTB2024NSCQ-MSX0483//Natural Science Foundation of Chongqing, China/ ; KJQN202200457//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; },
mesh = {Animals ; *Lysosomes/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics ; *tau Proteins/metabolism ; Mice ; Humans ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Histone Deacetylase 6/metabolism ; Hippocampus/metabolism/pathology ; },
abstract = {BACKGROUND: Impairment of lysosomal acidification has recently been identified as a critical driver of amyloid-β and MAPT/tau pathology in Alzheimer's disease (AD). Restoring lysosomal acidification is a promising strategy for AD treatment. N-deacetylase and N-sulfotransferase 3 (NDST3) is a newly discovered tubulin deacetylase that regulates lysosomal acidification by influencing the recruitment of V-ATPase V1 subunits to lysosomes. Nevertheless, the role of NDST3 in AD remains entirely unexplored.

METHODS: We began by comparing the effects of NDST3 and histone deacetylase 6 (HDAC6), a well-known tubulin deacetylase with established roles in AD, on lysosomal acidification. Using HT22 cell-based models of AD, we knocked down NDST3 to examine its role in lysosomal acidification and degradative function in the context of this disease. We also evaluated the expression profile of NDST3 in both in vitro and in vivo models of AD. Finally, we investigated the consequences of NDST3 suppression on lysosomal acidity and related AD pathological features in the hippocampi of 3 × Tg-AD mice.

RESULTS: NDST3 differs from HDAC6 in the subcellular spatial patterns of catalyzing microtubule deacetylation but parallels HDAC6 in regulating lysosomal pH. In HT22 cells with APP695[Swe] overexpression, knockdown of NDST3 lowered lysosomal pH by promoting the assembly of the V-ATPase holoenzyme on the lysosomal membrane and enhanced the autophagic degradation of aberrant Aβ and MAPT/tau. Notably, NDST3 levels were found to be elevated in the brains of AD models and patients. Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits.

CONCLUSIONS: Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Suppressing NDST3 restores lysosomal function in AD and protects against AD pathology, highlighting NDST3 as a promising therapeutic target for AD.},
}

Animals
*Lysosomes/metabolism/pathology
*Alzheimer Disease/metabolism/pathology/genetics
*tau Proteins/metabolism
Mice
Humans
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Histone Deacetylase 6/metabolism
Hippocampus/metabolism/pathology

@article {pmid42015324,
year = {2026},
author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC},
title = {Divergent patterns of cognitive decline in preclinical Alzheimer's disease: Implications for secondary prevention trials.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71366},
doi = {10.1002/alz.71366},
pmid = {42015324},
issn = {1552-5279},
support = {//Epstein Family Foundation/ ; //Avid Radiopharmaceuticals/ ; //GHR Foundation/ ; //Foundation for the National Institutes of Health/ ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; U24AG057437/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/prevention & control ; Aged ; Positron-Emission Tomography ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; Biomarkers ; *Secondary Prevention ; Disease Progression ; Prodromal Symptoms ; Hippocampus/pathology/diagnostic imaging ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Biomarkers identify Alzheimer's disease pathology in cognitively unimpaired adults, but the timing and rate of cognitive decline vary widely. This study aimed to identify subgroups of cognitive decline and baseline predictors of heterogeneity in preclinical progression.

METHODS: Data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study, which enrolled amyloid beta-positive (Aβ+) participants, and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, which enrolled amyloid beta-negative (Aβ-) individuals. Latent class mixed-effects models identified cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker variables were evaluated. The primary outcome was change in the Preclinical Alzheimer Cognitive Composite.

RESULTS: Three trajectory classes were identified: stable, slow decliners, and fast decliners. Higher phosphorylated tau at 217 (p-tau217), smaller hippocampal volume, and elevated tau positron emission tomography were associated with declining classes. About 70% of Aβ+ individuals were stable.

DISCUSSION: Latent class modeling reveals substantial heterogeneity in preclinical trajectories with important implications for prevention trial design.},
}

Humans
*Alzheimer Disease
Male
Female
*Cognitive Dysfunction/diagnostic imaging/prevention & control
Aged
Positron-Emission Tomography
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Longitudinal Studies
Biomarkers
*Secondary Prevention
Disease Progression
Prodromal Symptoms
Hippocampus/pathology/diagnostic imaging
Neuropsychological Tests

@article {pmid42015334,
year = {2026},
author = {van Etten, ES and Mahinrad, S and Grill, JD and Salloway, S and Atri, A and Cogswell, PM and Benzinger, TLS and Iwatsubo, T and Iadecola, C and Lemere, CA and Nicoll, JAR and Greenberg, SM and Carrillo, MC and Jack, CR and Sperling, RA},
title = {Amyloid-related imaging abnormalities (ARIA) in anti-amyloid therapies for Alzheimer's disease: An update from the Alzheimer's Association ARIA workgroup.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71361},
doi = {10.1002/alz.71361},
pmid = {42015334},
issn = {1552-5279},
support = {09150162410011/ZONMW_/ZonMw/Netherlands ; 642991//Alzheimer Nederland/ ; R01NS136122/NH/NIH HHS/United States ; R01AG084531/NH/NIH HHS/United States ; P30AG066519/NH/NIH HHS/United States ; P01AG003991/NH/NIH HHS/United States ; ARUK-PPG2023B-023//Alzheimer Research UK/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/therapy/metabolism ; *Neuroimaging/methods ; *Brain/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; *Amyloid/metabolism ; },
abstract = {In 2011, a workgroup of the Alzheimer's Association Research Roundtable introduced recommendations for detecting and monitoring amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease (AD) clinical trials. Since then, anti-amyloid immunotherapies have received regulatory approval for AD treatment and are beginning to enter clinical practice, underscoring the importance of informing healthcare providers, researchers, and patients about ARIA's implications in real-world settings. In response, the Alzheimer's Association convened a new workgroup to review current knowledge of ARIA, including underlying mechanisms, clinical presentations, associated risk factors, mitigation strategies, radiologic detection methods, patients' perspectives in treatment decision-making, and outstanding challenges. Here, we outline key insights from this workgroup, highlighting that effective ARIA detection and monitoring in clinical practice requires adherence to robust protocols to mitigate risks and enhance patient safety. Limited availability of clinical and pathologic data on predictors of symptomatic and severe ARIA underscores the importance of continued real-world data collection.},
}

Humans
*Alzheimer Disease/diagnostic imaging/drug therapy/therapy/metabolism
*Neuroimaging/methods
*Brain/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
*Amyloid/metabolism

@article {pmid42015793,
year = {2026},
author = {Gao, L and Watson, R and Yassi, N},
title = {Cost-Effectiveness of Donanemab for Early Alzheimer Disease in Australia.},
journal = {The Medical journal of Australia},
volume = {224},
number = {4},
pages = {e70186},
doi = {10.5694/mja2.70186},
pmid = {42015793},
issn = {1326-5377},
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Cost-Benefit Analysis ; Australia ; Quality-Adjusted Life Years ; Aged ; Markov Chains ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Male ; Disease Progression ; Female ; Amyloid beta-Peptides ; },
abstract = {OBJECTIVES: To evaluate the cost-effectiveness of donanemab, an anti-amyloid-β monoclonal antibody recently approved in Australia, for treating early-stage Alzheimer disease with confirmed amyloid-β pathology from healthcare system and societal perspectives.

DESIGN: A Markov microsimulation model simulating long-term Alzheimer disease progression, treatment costs and health outcomes for donanemab compared with standard care.

SETTING, PARTICIPANTS: Australian healthcare context, applying published clinical and economic inputs. A hypothetical cohort of people with early symptomatic Alzheimer disease, consistent with TRAILBLAZER-ALZ eligibility criteria: mean age 75 years, amyloid-β-positive, with mild cognitive impairment or mild dementia because of Alzheimer disease and excluding individuals with APOEE4 homozygotes, in line with the Australian labelling. Donanemab administered every 4 weeks with magnetic resonance imaging (MRI)-based amyloid-β-related imaging abnormalities monitoring and treatment suspension upon amyloid-β clearance or progression to severe Alzheimer disease, compared with standard care.

MAIN OUTCOME MEASURES: Incremental costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Secondary analyses included sensitivity and distributional equity analyses.

RESULTS: Donanemab increased total healthcare costs ($300,689 vs. $178,121) and societal costs ($389,113 vs. $283,618) compared with standard care per capita, while improving health outcomes (4.38 vs. 4.01 QALYs) per capita. The ICER was $342,424 per QALY from the healthcare perspective and $294,701 per QALY from the societal perspective, exceeding frequently cited Australian willingness-to-pay thresholds. Sensitivity analyses identified drug cost and efficacy as key drivers of uncertainty. Distributional analysis suggested inequitable health gains by remoteness because of differences in diagnostic and treatment infrastructure.

CONCLUSION: Donanemab provides clinical benefits but is unlikely to be cost-effective under current Australian thresholds. Policymakers should balance economic evidence with unmet need, equity considerations and healthcare sustainability when making reimbursement decisions. Further research using real-world evidence and disaggregated analyses by geography and socioeconomic status is warranted.},
}

Humans
*Alzheimer Disease/drug therapy/economics
Cost-Benefit Analysis
Australia
Quality-Adjusted Life Years
Aged
Markov Chains
*Antibodies, Monoclonal, Humanized/economics/therapeutic use
Male
Disease Progression
Female
Amyloid beta-Peptides

@article {pmid42015806,
year = {2026},
author = {Zhang, X and Elmansy, R},
title = {Exploring Influencing Factors of Medication Adherence Among Chinese Patients With Alzheimer Disease: Delphi Study Informing Future Artificial Intelligence-Supported Interventions.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e89508},
doi = {10.2196/89508},
pmid = {42015806},
issn = {2561-326X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Delphi Technique ; *Artificial Intelligence ; Male ; Female ; China ; *Medication Adherence/psychology ; Aged ; Middle Aged ; East Asian People ; },
abstract = {BACKGROUND: Alzheimer disease (AD) affects cognition, treatment adherence, family connections, and health care resource allocation. Most patients with AD have low adherence to medication therapy due to the limitations associated with cognitive impairment. Therefore, increasing the involvement of patients and their family members in medication management is important to improve treatment outcomes and reduce the burden of care.

OBJECTIVE: This study explores the potential application of artificial intelligence (AI) in medication management for Chinese patients with early- to mid-stage AD focusing on enhancing medication adherence. The study first predicts and evaluates key factors through an online Delphi study, which provides a basis for their subsequent incorporation into the AI model as input variables to enable prediction of medication-taking behaviors. Since AI research in medication management for this population is still undeveloped, this paper further explores the multiple potentials of AI from a theoretical view, including drug dosage optimization, multidrug interaction detection, and family education support. It will provide a preliminary direction and theoretical basis for the development of an intelligent medication management system in the future.

METHODS: The exploratory online Delphi study with no modification predicted the key factors influencing medication adherence. Based on the results, the study confirmed the potential of AI to improve adherence. Participation by 12 experts in 3 rounds systematically assessed the core elements influencing patients' adherence to their medication.

RESULTS: Family care, social support, environmental factors, emotional support, and patient behaviors were identified as the primary factors influencing medication adherence among Chinese patients with AD. These factors were validated and ranked through iterative Delphi rounds, with family care and social support receiving the highest importance scores. The Wilcoxon signed-rank test indicated no significant difference between rounds (P=.06), supporting the stability of the consensus. These findings establish a foundational set of variables for AI systems that predict and enhance medication adherence.

CONCLUSIONS: This study highlights the critical factors affecting medication adherence by Chinese patients with AD. It was designed as an exploratory online Delphi study to identify and prioritize key influencing factors, rather than to validate a specific AI-based system, and the findings provide a theoretical foundation for future AI-informed interventions. The results also indicate theoretical potential roles for AI in supporting medication management, such as optimizing drug dosage, detecting multidrug interactions, and enhancing family education.},
}

Humans
*Alzheimer Disease/drug therapy/psychology
Delphi Technique
*Artificial Intelligence
Male
Female
China
*Medication Adherence/psychology
Aged
Middle Aged
East Asian People

@article {pmid42016208,
year = {2026},
author = {Shah, KB and Xiang, L and Shah, SK and Adler, RR and Weissman, JS},
title = {Dementia Is Associated With Higher One-Year Mortality and Worse Patient-Centered Outcomes in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction and Cardiogenic Shock.},
journal = {Cardiology research},
volume = {17},
number = {2},
pages = {128-135},
pmid = {42016208},
issn = {1923-2829},
abstract = {BACKGROUND: Recent trial data demonstrates improved outcomes for the treatment of ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock (CS) with percutaneous coronary intervention (PCI) supported by mechanical circulatory support (MCS). Clinical outcomes in patients with Alzheimer's disease and related dementias (ADRD), however, remain unknown, as these patients were excluded from relevant trials. Physicians and caregivers struggle to navigate time-sensitive decision making for patients with ADRD presenting with STEMI or CS. The aims of this study were to assess the association of ADRD with outcomes of PCI with MCS in the setting of STEMI or CS.

METHODS: We compared outcomes among Medicare fee-for-service (FFS) beneficiaries aged 66 years or older, with and without ADRD, who underwent PCI with MCS for STEMI or CS from July 1, 2017 to December 31, 2019. The primary clinical outcome was inpatient mortality, and secondary clinical outcomes were 1-year mortality, complications, and readmissions. Patient-centered outcomes were time-at-home ratio and discharge to a higher level of care.

RESULTS: A total of 13,110 patients undergoing PCI with MCS for STEMI or CS met study criteria, and 988 (7.5%) patients carried a diagnosis of ADRD. Patients with ADRD were more likely to be older (81.1 vs. 75.5, P < 0.001) and frail (47.0% vs. 22.0%, P < 0.001). Inpatient mortality was similar between groups (odds ratio (OR), 1.05; 95% confidence interval (CI), 0.92-1.21), but 1-year mortality was higher among patients with ADRD (OR, 1.41; 95% CI, 1.21-1.64). Major complications and readmissions were similar between groups. Patients with ADRD were more likely to be discharged to a higher level of care (OR, 1.46; 95% CI, 1.16-1.82) than those without ADRD but demonstrated a similar time-at-home ratio.

CONCLUSIONS: Patients with ADRD demonstrate similar rates of inpatient mortality and major complications but have higher rates of 1-year mortality and discharge to higher levels of care.},
}

@article {pmid42016241,
year = {2026},
author = {Sun, M and He, J and Song, H and Ma, Z and Zhang, X and Li, J and Yao, Y},
title = {Structural Characterization and Anti-Alzheimer's Disease Effect of Polysaccharides From Stellariae Radix.},
journal = {Food science & nutrition},
volume = {14},
number = {3},
pages = {e71604},
pmid = {42016241},
issn = {2048-7177},
abstract = {Stellariae Radix, a frequently employed traditional Chinese medicine, originates from the dried roots of Stellaria dichotoma L. var. lanceolata Bge. To elucidate the structural characteristics and anti-Alzheimer's disease (AD) efficacy of S. dichotoma polysaccharides (SDP), SDP was extracted and comprehensively characterized using ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) spectroscopy and high-performance liquid chromatography (HPLC). The results revealed that SDP is composed of galactose, glucose, arabinose, galacturonic acid, mannose, and rhamnose at a molar ratio of 5.561:2.224:0.802:0.616:0.613:0.184. In vitro experiments demonstrated that SDP exhibited potent scavenging activities against ABTS, DPPH, and hydroxyl radicals in a dose-dependent manner, with the average scavenging rates reaching 99.07%, 89.44% and 56.43% respectively at the concentration of 5 mg/mL. In a C57BL/6J mouse model of AD, administration of SDP (50-200 mg/kg) significantly ameliorated cognitive dysfunction, increased the hippocampal levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the malondialdehyde (MDA) content, and regulated the expression of oxidative stress-related proteins, including Nrf2, Keap1 and NQO1. These findings indicate that SDP possesses antioxidant and neuroprotective properties, suggesting its potential therapeutic value for the treatment of AD.},
}

@article {pmid42016382,
year = {2026},
author = {Yi, S and Zou, J and He, X and Chen, H and Lin, Z and Zhang, L and Zhu, Y and Zuo, Z and Chen, Z and Hu, X and Niu, L},
title = {Transcranial Ultrasound Stimulation Pulsed at 40 Hz Improves Cognition and Neuroinflammation in Female Mice with Alzheimer's Disease.},
journal = {Research (Washington, D.C.)},
volume = {9},
number = {},
pages = {1244},
pmid = {42016382},
issn = {2639-5274},
abstract = {Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer's disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm[2] yielded the optimal cognitive outcome in Alzheimer's disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1, phosphorylated NF-κB, and necroptosis markers, alongside reductions in key pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1/NF-κB signaling.},
}

@article {pmid42018938,
year = {2026},
author = {Haghighi, FH and Xie, J and Ebert, ET and Siahaan, TJ},
title = {Progress and challenges in drug delivery for the treatment of Alzheimer's disease.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2026.2663114},
pmid = {42018938},
issn = {1744-7593},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder marked by declining memory and cognitive function. Despite recent advances to slowdown early-stage progression, no curative therapies exist due to challenges in delivering neuroregenerative agents to the brain.

AREAS COVERED: This review examines recent research on strategies to modulate the blood-brain barrier (BBB) to enhance delivery of small-to-large molecules through the paracellular pathway into the brain for potential treatments of AD. A literature search was conducted using PubMed and Scopus covering studies published between 2016 and 2026.

EXPERT OPINION: BBB modulation technologies are advancing rapidly and offer real potential to improve delivery of therapeutics in AD patients. Hyperosmotic method has been successfully used to deliver anticancer drugs to treat brain tumor patients and can be used for AD. Recently, focused ultrasound (FUS) has been used to disrupt the BBB at a targeted brain region to enhance paracellular permeation of drug molecules to the brain. Finally, drug permeation through the BBB paracellular pathway can also be enhanced by modulating the protein-protein interactions in the intercellular junctions using BBB modulators (BBBMs). This review covers the mechanisms, advantages, and limitations of these methods as well as recent studies to enhance therapeutic agents for AD and other brain diseases.},
}

@article {pmid42019114,
year = {2026},
author = {Liu, Y and Jiang, Z and Chen, D and He, Z and Ning, W and Wang, S and Guan, L},
title = {Design, synthesis, and biological evaluation of Chromene-Phenylpiperazine-Chalcone hybrids as multi-target-directed ligands for the treatment of Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry},
volume = {138},
number = {},
pages = {118670},
doi = {10.1016/j.bmc.2026.118670},
pmid = {42019114},
issn = {1464-3391},
abstract = {A novel series of chromene-phenylpiperazine-chalcone hybrids was rationally designed, synthesized and evaluated as multi-target-directed ligands (MTDLs) for Alzheimer's disease (AD). Among them, compound 9 s exhibited selective equine serum butyrylcholinesterase (eqBuChE, IC50 = 0.13 μM) and concurrent monoamine oxidase B (MAO-B, IC50 = 1.63 μM) inhibitory activities. Kinetic and molecular docking studies indicated that 9 s acts as a mixed-type dual-site inhibitor. In silico modeling suggests that the binding pose is stabilized by a predicted pseudo-seven-membered ring. Furthermore, 9 s facilitated the disassembly of self-aggregated and Cu[2+]-induced Aβ1-42 fibrils. In BV-2 microglial cells, it demonstrated a high safety margin (> 380-fold effective concentration), accelerated intracellular Aβ clearance, and subsequently attenuated LPS-induced NO production. In vivo evaluations revealed low acute toxicity (LD50 > 1000 mg/kg). Oral administration of 9 s successfully reversed scopolamine-induced spatial working memory deficits in mice. These findings validate the drug-like 9 s as an orally efficacious MTDL candidate that provides symptomatic cognitive relief, while possessing promising in vitro disease-modifying potential for AD therapy.},
}

@article {pmid42019137,
year = {2026},
author = {Otani, K and Ishihara, H and Nakamura, T and Kawabe, K},
title = {Implementation and service impact of anti-amyloid therapy in a psychiatry-led dementia care program: Real-world evidence from a Japanese regional dementia center.},
journal = {General hospital psychiatry},
volume = {100},
number = {},
pages = {208-214},
doi = {10.1016/j.genhosppsych.2026.04.006},
pmid = {42019137},
issn = {1873-7714},
abstract = {BACKGROUND: Amyloid-targeting antibody therapies for Alzheimer's disease require substantial diagnostic infrastructure including amyloid PET imaging, repeated MRI monitoring, and specialized clinical evaluation. In Japan, psychiatrists frequently lead dementia diagnosis and treatment in general hospitals through designated Regional Dementia Medical Centers; however, the real-world service impact of implementing these therapies in psychiatry-led dementia care remains poorly described.

METHODS: We conducted a retrospective analysis of administrative and billing data from a Regional Dementia Medical Center at Kakogawa Central City Hospital, Japan. Data included amyloid PET imaging, anti-amyloid monoclonal antibody therapy (lecanemab and donanemab), and associated reimbursement and acquisition costs between May 2024 and January 2026. This study was conducted as part of institutional quality improvement activities.

RESULTS: During the observation period, 72 amyloid PET examinations were performed. Results were amyloid-positive in 50 cases (69%) and negative in 22 cases (31%). Of 50 amyloid-positive patients, 38 (76%) initiated anti-amyloid therapy (lecanemab: 14; donanemab: 24), with 389 total treatment administrations. ARIA was detected in 8 treated patients (21%), all asymptomatic. MRI examinations for ARIA monitoring increased from 5 in FY2023 to 58 in FY2024 and 139 in FY2025. Total reimbursement amounted to 35.4 million yen for lecanemab and 25.7 million yen for donanemab. Drug acquisition costs represented approximately 97% of reimbursement, with margins averaging 3%. Outpatient revenue per visit increased 141% from 5560 yen in FY2022 to 13,401 yen in FY2025, despite stable visit volumes (FY2022: 11,203; FY2024: 10,223).

CONCLUSIONS: Implementation of amyloid-targeting antibody therapy in psychiatry-led dementia care substantially increases service activity and hospital revenue streams but generates narrow financial margins due to high drug acquisition costs. All ARIA cases were asymptomatic, supporting the feasibility of systematic monitoring within a psychiatry-led model in this setting. These findings highlight important structural and economic considerations for the sustainability of these programs in general hospital psychiatry.},
}

@article {pmid42019901,
year = {2026},
author = {Tseng, CH},
title = {The hidden link between diabetes and dementia: Findings from recent epidemiological studies.},
journal = {Biomedical journal},
volume = {},
number = {},
pages = {100985},
doi = {10.1016/j.bj.2026.100985},
pmid = {42019901},
issn = {2320-2890},
abstract = {Recent epidemiological studies investigating the link between diabetes mellitus and dementia or Alzheimer's disease are narratively reviewed. Diabetes mellitus is associated with a significantly higher risk of dementia by 56%, more predominant for vascular dementia than Alzheimer's disease and tau pathology is more remarkable than amyloid β deposition. The increased risk is related to the burden of microvascular and macrovascular diseases in a dose-response pattern; and a threshold effect between glycemic control and dementia risk is observed. A treatment target of hemoglobin A1c < 7% may be optimal for reducing the risk of dementia but hypoglycemia should be avoided. Antidiabetic drugs such as metformin, pioglitazone, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists may show beneficial effects on dementia in observational studies. In a Taiwanese cohort study acarbose is also associated with a lower risk of dementia in female diabetes patients. When considering the repurposing of antidiabetic drugs in the treatment of patients with Alzheimer's disease, low-dose insulin detemir shows a promising effect in a network meta-analysis. A phase 3 clinical trial (MET-FINGER) is being conducted to investigate whether metformin plus lifestyle intervention can be effective in the prevention of Alzheimer's disease. Hyperuricemia, though considered a potential component of metabolic syndrome, seems to be associated with a lower risk of dementia. Sex hormones play some roles in cognitive function and females present a higher risk of dementia than males. However, additional studies are required to explore the impacts of sex and sex hormones on the development of dementia and Alzheimer's disease.},
}

@article {pmid42020091,
year = {2026},
author = {Mewton, L and Winter, V and Hoy, N and Visontay, R and Davies, S and Kochan, N and Baillie, A and Chapman, C and Newton, NC and Sunderland, M and Sachdev, PS and Teesson, M},
title = {Effect of the online Rethink My Drink alcohol intervention on alcohol use and cognition in older adults in Australia: a randomised controlled trial.},
journal = {The Lancet. Public health},
volume = {11},
number = {5},
pages = {e318-e328},
doi = {10.1016/S2468-2667(26)00056-3},
pmid = {42020091},
issn = {2468-2667},
mesh = {Humans ; Aged ; Male ; Female ; Middle Aged ; Australia/epidemiology ; *Alcohol Drinking/prevention & control/epidemiology ; *Cognitive Dysfunction/prevention & control ; *Cognition ; *Internet-Based Intervention ; },
abstract = {BACKGROUND: Alcohol use is increasing among older adults and is associated with cognitive impairment and dementia. The efficacy of scalable approaches to reduce alcohol use and related harms in older adults has not been tested. This study aimed to evaluate the efficacy of an online alcohol intervention in reducing alcohol use and cognitive decline in older adults.

METHODS: We did a two-arm, parallel-group, randomised controlled trial online among community-based older adults (aged 60-75 years) who screened as having high-risk alcohol use (scoring ≥5 on the Alcohol Use Disorder Identification Test). Exclusion criteria included diagnosis of a neurological disorder (eg, dementia, Parkinson's disease, or multiple sclerosis), previous prescription of medication for the treatment of Alzheimer's disease, and non-correctable visual impairment. Participants across Australia were randomly assigned (1:1) to the Rethink My Drink programme (a four-module online intervention designed specifically for older adults) or an active control group (online information booklet), stratified by age and gender. Participants and the lead statistician were masked to group assignment. Number of drinks in the past month and global cognition Z scores assessed via the Cambridge Neuropsychological Test Automated Battery were the primary outcomes, assessed at the 12-month follow-up. Intention-to-treat analyses were conducted using generalised mixed effects regression. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000292875; March 16, 2021), and is completed.

FINDINGS: Between Oct 29, 2021, and June 6, 2022, 3766 participants were screened for eligibility, 2878 were excluded (1390 did not meet inclusion criteria, 1047 declined to participate, and 441 had incomplete baseline assessments), and 888 completed baseline assessments and were randomly assigned. 448 participants were assigned to the Rethink My Drink intervention and 440 were assigned to receive the online patient information booklet. Data from 445 participants in the intervention group and 438 participants in the control group were analysed. Most participants (872 [99%] of 883) identified as White, 685 (78%) participants were female and 198 (22%) were male, and the mean age was 65·3 years (SD 3·9). At 12 months, those in the intervention group had greater reductions in their monthly number of standard drinks when compared with the control group (difference, 5·02 standard drinks [95% CI 1·81 to 8·24]; p<0·0001). For global cognition, the difference between the two groups was not significant at 12 months (difference 0·12 SDs [95% CI -0·05 to 0·29]; p=0·16). Two participants (one in the control group and one in the intervention group) spontaneously reported non-serious adverse events that were assessed as unrelated to the trial.

INTERPRETATION: Rethink My Drink is an effective and scalable intervention that has considerable potential for reducing alcohol use among older adults.

FUNDING: Dementia Centre for Research Collaboration.},
}

Humans
Aged
Male
Female
Middle Aged
Australia/epidemiology
*Alcohol Drinking/prevention & control/epidemiology
*Cognitive Dysfunction/prevention & control
*Cognition
*Internet-Based Intervention

@article {pmid42006351,
year = {2026},
author = {Abskharon, R and Jiang, YX and Sawaya, MR and Ge, P and Zhang, J and Boyer, DR and Dolinsky, JL and Pi, J and Cascio, D and Guo, F and Eisenberg, DS},
title = {Structural evidence that RNA contributes to polymorphism of tau amyloid fibrils.},
journal = {iScience},
volume = {29},
number = {4},
pages = {115501},
pmid = {42006351},
issn = {2589-0042},
abstract = {RNA colocalizes with tau deposits in Alzheimer's disease (AD) and drives tau aggregation in vitro. Previously, we determined a cryogenic-electron microscopy (cryo-EM) structure of fibrils of full-length tau bound to unfractionated mammalian RNA, revealing a small tau C-terminal core. Here, we present the cryo-EM structure of fibrils of full-length recombinant tau bound to unfractionated mammalian RNA seeded by AD-extracted tau fibrils. This structure reveals an expanded tau C-terminal core resembling AD tau fibrils. RNA sequencing identified 18S ribosomal RNA as the primary fibril-bound species. Next, we determined the cryo-EM structure of fibrils of full-length recombinant tau bound to mammalian 18S ribosomal RNA, revealing a core that consists of the R2 to R4 repeat domains previously seen in pathological tau fibrils. All our recombinant RNA-tau fibrils dissolve upon RNase treatment. Tau fibrils adopt distinct folds in the presence of different RNAs, suggesting RNA is a cofactor capable of shaping tau fibril polymorphism.},
}

@article {pmid42006409,
year = {2026},
author = {Davidson, MH and Hsieh, A and de Kleer, M and Szarek, MS and Scheltens, P and Vijverberg, E and Johnson, A and Ditmarsch, M and Kastelein, JJP},
title = {The emerging role of CETP inhibition in the prevention of Alzheimer's disease.},
journal = {American journal of preventive cardiology},
volume = {26},
number = {},
pages = {101442},
pmid = {42006409},
issn = {2666-6677},
abstract = {We recently showed that patients with atherosclerotic cardiovascular disease (ASCVD) carry a substantial but largely unrecognized burden of early Alzheimer's disease (AD) pathology. In the BROADWAY pivotal phase 3 lipid-lowering trial, nearly half of participants with high-risk ASCVD had plasma p-tau217 concentrations above thresholds associated with preclinical AD, yet none had undergone evaluation for cognitive impairment. In this population, apolipoprotein E ε4 (APOE4) carriers were disproportionately represented among those with the highest p-tau217 levels. These findings expose a critical gap between cardiovascular care and dementia prevention and raise the question whether interventions targeting shared pathophysiology could address both conditions simultaneously. Cholesteryl ester transfer protein (CETP) inhibition has emerged as a candidate for this dual role. In BROADWAY, obicetrapib reduced p-tau217 progression across the study population, with effects most pronounced in APOE4 carriers. In fact, treatment differences favoring obicetrapib were observed across all measured AD biomarkers in high-risk subgroups, including neurofilament light chain, glial fibrillary acidic protein, and the amyloid-beta (Aβ) 42:40 ratio. Unlike approaches that target downstream pathology, such as amyloid plaques already deposited in the brain or the inflammatory consequences of established disease, CETP inhibition may address the upstream processes involved in initiating the pathological cascade: lipid dysregulation, cholesterol ester accumulation in glial cells, impaired cholesterol efflux, lipid peroxidation, oxysterol formation, and deficient antioxidant transport. This review examines the biological rationale linking APOE4 status to disordered lipid metabolism in both peripheral and central compartments, the genetic and epidemiological evidence supporting CETP as a therapeutic target, the mechanisms through which CETP inhibition might confer neuroprotection, and the clinical data suggesting obicetrapib as the first oral agent associated with favorable changes in AD biomarkers across both amyloid and tau axes in individuals at high genetic risk for the development of AD.},
}

@article {pmid42006781,
year = {2026},
author = {Raikes, AC and Garza, M and Murrell, AN and Brinton, RD},
title = {Meta analysis of glucose metabolism across Alzheimer's, Parkinson's and ALS Reveals emergence of adaptive brain glucometabolic responses and associated neurological functional profiles.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.07.26350339},
pmid = {42006781},
abstract = {IMPORTANCE: Glucose metabolic dysregulation in brain is a common feature of late-onset age-associated neurodegenerative disease (A [2] ND). Prior meta-analyses have identified disease-specific effects compared to healthy, unimpaired individuals. Yet, a unifying A [2] ND glucose dysregulation spatial signature remains undescribed.

OBJECTIVE: To determine the common signature of dysregulated glucose metabolism on FDG-PET using activation likelihood estimation (ALE) meta-analyses across A [2] ND.

DATA SOURCES: Searches were conducted using MEDLINE, Embase, PsycINFO, Scopus, and Cochrane from inception through July 2025. The search terms included controlled vocabulary and keywords for four neurodegenerative diseases Parkinson Disease, Amyotrophic Lateral Sclerosis, Alzheimer Disease, and Multiple Sclerosis, Fluorodeoxyglucose F18, glucose, and positron-emission tomography (PET).

STUDY SELECTION: Studies comparing adults with late-onset neurodegenerative diseases to non-diseased controls using FDG-PET to quantify brain glucose uptake and reporting whole-brain coordinate findings in either Talairach or Montreal Neurological Institute space were included.

DATA EXTRACTION AND SYNTHESIS: Three researchers, assisted by an AI screening tool, screened 7275 potential titles and abstracts for inclusion. Full texts were then retrieved for potentially relevant articles and were evaluated by three researchers using prespecified inclusion/exclusion criteria.

MAIN OUTCOMES AND MEASURES: Cluster peak and subpeak coordinates, cluster-wise t-or Z-values, and annotations indicating the disease of interest, whether the outcome was for hyper-(disease group > control) or hypometabolism (disease group < control), were extracted from included texts and analyzed using ALE.

RESULTS: A total of 130 FDG-PET studies were included in the meta-analysis, with a combined sample of 5298 individuals with A [2] ND and 3499 controls. Meta-analyses revealed dysregulated glucose metabolism as a unifying feature across A [2] ND which included both hypo-and hypermetabolic patterns. Neuroanatomical metabolic pattern was unique and disease specific. Each A [2] ND metabolic phenotype was associated with unique and complex patterns of neurological functionalities.

CONCLUSIONS AND RELEVANCE: These data demonstrate dysregulated glucose metabolism as a common A [2] ND feature, suggesting responsive remodeling of neural bioenergetics. While hypometabolism is a common research focus, due to functional relevance, hypermetabolism may reflect a compensatory, maladaptive, or neuroinflammatory signal, that requires focused investigation. A [2] ND prevention and treatment efficacy may depend on addressing bidirectional metabolic dysregulation in addition to disease-specific drivers of pathology.},
}

@article {pmid42008282,
year = {2026},
author = {Burns, JM and Woodward, JL and Morris, JK and Townley, RA},
title = {Reimagining Care Delivery for Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0801},
pmid = {42008282},
issn = {2168-6157},
}

@article {pmid42008483,
year = {2026},
author = {Zhang, X and Wang, Z and Sun, M and Bao, Q and Chen, Z and Liu, Y and Wang, Z and Ye, F and Yang, Z and Du, X and Zhang, H and Mou, X and He, X and Li, D and Wu, K and Yao, J and Zhong, W and Xu, P and Yang, S and Zhao, L and Yin, Z and Liang, F},
title = {Acupuncture for amnestic mild cognitive impairment: Study protocol for a multicenter, single-blinded, long-term, randomized controlled trial.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0346717},
doi = {10.1371/journal.pone.0346717},
pmid = {42008483},
issn = {1932-6203},
mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Single-Blind Method ; Aged ; Female ; Male ; Treatment Outcome ; *Amnesia/therapy ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI), a common neurodegenerative disease affecting older adults, has garnered significant research interest over the past few years. While previous studies have suggested that acupuncture holds promise as a clinical intervention to improve cognitive function in patients with aMCI, the long-term effect of acupuncture treatment for aMCI remains unclear.

METHODS: This is a multicenter, single-blinded, randomized controlled trial (RCT) with a long-term follow-up.166 patients diagnosed with aMCI will be randomly divided into acupuncture group (AG) and sham acupuncture group (SA). The intervention will last for 12 weeks (2 sessions per week), follow-up for 48 weeks, and the study will last a total of 60 weeks. The primary outcomes are the changes in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score from baseline to week 12 and from baseline to week 60. Generalized estimating equations (GEE) will be used to assess the impact of the acupuncture intervention on outcome variables over time at baseline and weeks 12, 24, 48, and 60.

DISCUSSION: This protocol outlines a detailed procedure for a multicenter RCT designed to further evaluate the long-term effect of acupuncture in managing aMCI. We anticipate that the findings of this research will provide valuable insights and evidence-based recommendations for the clinical management of this patient population.

TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Registry on 28 May 2024 (Number: ChiCTR2400084932).},
}

Humans
*Cognitive Dysfunction/therapy
*Acupuncture Therapy/methods
Single-Blind Method
Aged
Female
Male
Treatment Outcome
*Amnesia/therapy
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
Middle Aged
Aged, 80 and over

@article {pmid42008564,
year = {2026},
author = {Al-Anbari, E and Karshenas, H and Shoushtarian, B},
title = {Normalizing flow based neural processes for Alzheimer's disease progression prediction.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0345958},
doi = {10.1371/journal.pone.0345958},
pmid = {42008564},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Aged ; Male ; Female ; Neuroimaging ; },
abstract = {As one of the most common neurodegenerative diseases, Alzheimer's accounts for serious health problems worldwide. Accurate detection and prediction of this disease contribute to the health system for better prevention and interventions in the treatment plans. However, traditional models designed for prediction and classification face several challenges, including handling complex data, which neglects many data points for the diagnosis. To overcome this challenge, we propose a novel model based on the integration of Neural Processes (NPs) and Normalizing Flows (NFs). The dataset used for this study is the Alzheimer's Disease Prediction of Longitudinal Evolution (TADPOLE). We selected various features to build an efficient model, including cognitive, neuroimaging, genetic, and demographic data. which contains three classes: Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD. The proposed model is able to capture the temporal dependencies present in the complex distribution. The stochastic processes were modeled by NPs, while NF was able to transform the Gaussian distributions from simple to complex distributions, allowing them to model a wide range of data distributions. The prediction performance and robustness have been enhanced since this framework is able the adapt to every patient trajectory and generalizing across different populations. The model was compared with other models, such as SNP, deep geometric learning, Manifold DCNN, and other models. Our model (SNP-NF) made an improvement regarding mAUC, Precision, and Recall, approximately 3%,1%, and 0.7%, respectively from our previous model, which utilized only NP. These results demonstrate the capability of the proposed approach to provide early detection and personal treatment plans for patients suffering from this disease.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology/pathology/genetics
Disease Progression
Cognitive Dysfunction/diagnosis
Aged
Male
Female
Neuroimaging

@article {pmid42009326,
year = {2026},
author = {Garg, A and Shaw, R},
title = {SSiamese Capsule Network (SNNCap) : Cognitive Analysis for Alzheimer's Disease Classification from MRI Data.},
journal = {IEEE transactions on image processing : a publication of the IEEE Signal Processing Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TIP.2026.3683547},
pmid = {42009326},
issn = {1941-0042},
abstract = {Alzheimer's Disease (AD) detection is essential for timely treatment and better patient care. Magnetic Resonance Imaging (MRI) is a technique in which radio waves and magnetic fields are used to capture high-resolution, multi-dimensional representations of brain structures. This high-resolution imaging capability makes MRI a key tool for diagnosing neurological disorders such as Alzheimer's disease. However, the problem is to correctly classify the fresh MRI scans of patients. Researchers have proposed a deep learning-based method for Alzheimer's disease diagnosis using a Siamese Convolutional Neural Network (SCNN) with three ResNet-34 branches trained on structural MRI data. However, this method relies solely on ResNet34 for feature extraction which struggles to preserve spatial relationship due to pooling operations, causing loss of positional information. Other researchers have explored methods like attention mechanisms and 3D convolutional networks to capture spatial dependencies. However, these methods underperform by missing brain complexity or needing high resources without consistent accuracy. In this study, we propose a cognitively inspired approach for classifying MRI images as Non Demented, Very Mild Demented, Mild Demented and Moderate Demented using Siamese Capsule Network (SNNCap). SNNCap uses ResNet-18 for feature extraction and capsule layers to preserve spatial and part-whole relationships in the images. It compares a test image against a few known reference examples per class. This reference-based validation closely mimics cognitive reasoning, improving the system's generaliz-ability. The model achieves strong results on unseen data and demonstrates its effectiveness through classification reports and confusion matrices.},
}

@article {pmid42009978,
year = {2026},
author = {Wang, L and Venkatesh, S and Morris, M and Li, M and Srivastava, R and Visweswaran, S and Lopez, OL and Xia, Z and Cai, T},
title = {Stratification of Alzheimer's disease patients using knowledge-guided unsupervised latent factor clustering with electronic health record data.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01511-y},
pmid = {42009978},
issn = {2730-664X},
abstract = {BACKGROUND: Prognostication for people with Alzheimer's disease (AD) at the point of care could improve clinical management.

METHODS: In this retrospective cohort study using the electronic health record (EHR) data from a large healthcare system (2011-2022), we applied an unsupervised latent factor clustering approach guided by knowledge graph embeddings to stratify AD patients into two groups at diagnosis (baseline) using clinical features in the two years preceding diagnosis. We prognosticated the risk of AD-related outcomes (nursing home admission and mortality) for the clusters in survival analyses adjusted for baseline confounders (age, gender, race, ethnicity, healthcare utilization, and comorbidities). To reflect real-world evolution in clinical trajectories, we updated patient stratification for patients remaining at risk one year post-diagnosis and repeated prognostication.

RESULTS: We stratify 16,411 AD patients into two groups at baseline (41% Group 1, 59% Group 2). Baseline Group 2 has a significantly lower risk of nursing home admission (HR [95% CI] = 0.804 [0.765, 0.844], p < .001) but comparable mortality risk to baseline Group 1 (HR [95% CI] = 1.008 [0.963, 1.056], p = 0.733). We re-stratify the 12,606 patients remaining at risk one year post-diagnosis (46% Group 1, 54% Group 2). Consistent with baseline, the updated Group 2 has a lower risk of nursing home admission (HR [95% CI] = 0.815 [0.766, 0.868], p < .001) but comparable mortality risk (HR [95% CI] = 0.977 [0.922, 1.035], p = .430) to Group 1.

CONCLUSIONS: Patient stratification enables outcome prognosis for AD patients. While baseline prognostication can guide early treatment and tailored management, dynamic prognostication may inform more timely interventions to improve long-term outcomes.},
}

@article {pmid42009995,
year = {2026},
author = {Tan, JY and Retinasamy, T and Lee, VLL and Radhakrishnan, AK and Yeong, KY},
title = {Exploring the role of tocotrienol-rich fraction (TRF) in ameliorating neuroinflammation.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42009995},
issn = {1568-5608},
abstract = {Neuroinflammation is a chronic inflammatory response that contributes to synaptic dysfunction and neuronal damage, it is a common feature among various neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and Huntington's Disease (HD). Tocotrienol-rich fraction (TRF) is a form of vitamin E that is known for its anti-inflammatory, antioxidant and neuroprotective properties. Yet, it has not been adequately investigated in both cellular and animal neuroinflammation models. In this study, the potential therapeutic effects of TRF were investigated in-vitro using BV2 microglial cells and also in-vivo in a pilot study using Sprague Dawley rats. TRF at 5 and 10 µg/mL were found to reduce nitric oxide (NO) and reactive oxygen species (ROS) levels. Furthermore, in-vivo treatment with TRF significantly increases the recognition index implying improvement in cognition ability. Gene expression analysis showed downregulation of RelA, TNF-α and IL-6 while NFE2L2 and BDNF were upregulated. These findings suggests that TRF may help mitigates neuroinflammation and oxidative stress, indicating its potential as a candidature for further investigation in neurodegenerative diseases associated with chronic neuroinflammation.},
}

@article {pmid42010230,
year = {2026},
author = {Liu, Y and Kunutsor, SK},
title = {Brain, benefit, or burden? Revisiting statins and cognitive function in older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42010230},
issn = {2509-2723},
abstract = {Statins are among the most widely prescribed medications for the prevention and treatment of cardiovascular disease, particularly in older adults. However, concerns regarding their potential adverse cognitive effects, including memory loss and dementia, have generated substantial debate and regulatory attention. This narrative review critically appraises current evidence on the relationship between statin use and cognitive outcomes in older adults, exploring both potential risks and benefits. We synthesized findings from randomized controlled trials (RCTs), observational cohort studies, meta-analyses, and Mendelian randomization studies. We also examined biological mechanisms, subgroup differences by statin type, and clinical considerations specific to older populations. Most RCTs have not demonstrated a harmful effect of statins on cognition, while observational studies have shown mixed results, including possible protective associations. Mechanistically, statins may exert both neuroprotective and neurotoxic effects, depending on their type, dose, and ability to cross the blood-brain barrier. Mendelian randomization analyses, including those involving over 100,000 individuals from the Danish general population, have largely found no causal effect of genetically proxied statin targets on dementia or neurodegenerative diseases. Importantly, older adults remain underrepresented in trials with cognitive outcomes, and real-world evidence is limited by confounding. Two large-scale randomized trials, PREVENTABLE and STAREE, are currently underway and poised to provide definitive evidence regarding the cognitive effects of statins in older populations. Current evidence does not support discontinuing statin therapy in older adults based solely on concerns about cognitive decline. Instead, decisions should be individualized, weighing cardiovascular benefit against cognitive risk, particularly in those with pre-existing cognitive impairment, polypharmacy, or frailty. Future research should prioritize cognition as a primary outcome in studies involving older populations.},
}

@article {pmid42011226,
year = {2026},
author = {Weiss, B and Miranda, DR and Arrazati, D and Cao, R and Chen, J and Liu, Y and Brown, D and Marshall, G},
title = {SRN-901, a Novel Longevity Drug, Extends Lifespan and Healthspan by Targeting Multiple Aging Pathways.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {594895},
pmid = {42011226},
issn = {1177-8881},
mesh = {Animals ; *Longevity/drug effects ; Mice ; *Aging/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Niacinamide/analogs & derivatives/pharmacology ; },
abstract = {INTRODUCTION: Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901-a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820-on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet.

RESULTS: SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (D-14) and post-treatment (D128; p < 0.001). Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health.

DISCUSSION: These results highlight SRN-901 as a promising multi-compound candidate for extending lifespan and healthspan by targeting multiple aging pathways.},
}

Animals
*Longevity/drug effects
Mice
*Aging/drug effects/metabolism
Male
Mice, Inbred C57BL
Niacinamide/analogs & derivatives/pharmacology

@article {pmid42011967,
year = {2026},
author = {Nowell, J and Crook, H and de Leon, MJ and Edison, P},
title = {Advances in the drug treatment of Alzheimer's disease: pathophysiology and mechanisms of action.},
journal = {BMJ (Clinical research ed.)},
volume = {393},
number = {},
pages = {78881},
doi = {10.1136/bmj-2023-078881},
pmid = {42011967},
issn = {1756-1833},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/pathology/metabolism ; },
abstract = {Alzheimer's disease, the leading cause of dementia, is a multifactorial disorder involving amyloid beta (Aβ) and tau deposition, impaired glucose metabolism, neuroinflammation, mitochondrial dysfunction, insulin resistance, and progressive brain atrophy. Anti-Aβ therapies have shown clinical efficacy and are licensed in several countries. Amyloid related imaging abnormalities remain a key safety concern, and reimbursement varies across healthcare systems. The mechanisms underlying continued cognitive decline after Aβ clearance remain unclear and might be independent of amyloid pathology. Because Alzheimer's disease involves multiple pathological processes, effective management will likely require combination treatments addressing tau aggregation, neuroinflammation, synaptic loss, and metabolic dysfunction. Numerous compounds targeting these mechanisms are currently in late stage development for both early and advanced disease. These emerging approaches represent a shift toward multimodal, disease modifying strategies designed to improve patient outcomes and quality of life. Here, we review recent therapeutic advances in Alzheimer's disease and provide perspectives on novel treatment strategies.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Brain/pathology/metabolism

@article {pmid42012375,
year = {2026},
author = {Nakashima, S and Sato, K and Niimi, Y and Aso, S and Yasunaga, H and Satake, W and Iwatsubo, T},
title = {Early adoption of lecanemab in Japan (December 2023-December 2024): Pretreatment diagnostic timelines from the DeSC claims database.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443634},
doi = {10.1177/13872877261443634},
pmid = {42012375},
issn = {1875-8908},
abstract = {Using the Japanese DeSC claims database, we described pretreatment timelines for lecanemab initiation during early rollout (December 2023-December 2024). We identified 76 patients (mean age 74.6 years; 34.2% men) from 45 institutions. Mean time to first infusion was 103.9 days from cognitive assessment and 63.1 days from MRI. PET-to-infusion was 30.9 days, whereas cerebrospinal fluid (CSF) sampling-to-infusion was 85.8 days; the post-test interval remained longer after CSF (Bonferroni-adjusted p = 0.015). Although this claims-based snapshot may not represent all practice in Japan, it suggests that the CSF-based pathway can be associated with a longer post-test interval before treatment initiation.},
}

@article {pmid42012388,
year = {2026},
author = {Hildebrandt, H and Duning, T and Holland-Letz, M},
title = {Is there a cognitive measure of neurodegeneration for amyloid-Aβ-ratio probable Alzheimer's disease patients?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444308},
doi = {10.1177/13872877261444308},
pmid = {42012388},
issn = {1875-8908},
abstract = {BackgroundRecent developments in the assessment of Alzheimer's disease (AD) have centered on differential diagnostic questions. Only a few studies have aimed to identify neuropsychological measures that allow the prediction of disease progression. However, this question is central to informing patients about their diagnosis and to decisions regarding the urgency and timing of treatment escalation.ObjectiveWe analyzed which, if any, neuropsychological test results reflect the extent of neurodegenerative progression.MethodsThis retrospective analysis included 290 patients divided into an Aβ-ratio + group (n = 146; AD biomarker profile) and an Aβ-ratio- group (n = 144; non-AD biomarker profile). The Aβ-ratio + group was further divided into four t-tau quartiles. The Aβ-ratio- group was subdivided into patients with normal (n = 94) or elevated t-tau (n = 50).ResultsRegression and variance analyses demonstrated a correlation between Trail Making Test B (TMT-B) performance and t-tau levels in patients with an Aβ-ratio+, driven by differences between low and high tau values, but not in Aβ-ratio- patients. Several additional statistical control analyses endorsed this finding.ConclusionsWe conclude that, for Aβ-ratio + patients, TMT-B performance may serve as a clinically accessible indicator of tau-related disease activity and the extent of neurodegeneration and may help identify patients at risk of faster progression if replicated in longitudinal studies.},
}

@article {pmid42012422,
year = {2026},
author = {Xu, R and Ma, X and Wu, L and Yin, D and Zhao, L and Zhou, M and Yao, Y and Lin, R and Li, W and Yu, K},
title = {Transcranial Direct Current Stimulation Improves Cognitive Dysfunction in Amyloid Precursor Protein/Presenilin 1 Mice by Promoting Alternative Polarization of Microglia and Amyloid-Β Degradation.},
journal = {Neuromodulation : journal of the International Neuromodulation Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurom.2026.03.007},
pmid = {42012422},
issn = {1525-1403},
abstract = {OBJECTIVE: This study investigated the mechanisms by which transcranial direct current stimulation (tDCS) alleviated Alzheimer's disease (AD) progression.

MATERIALS AND METHODS: Amyloid precursor protein (APP)/human presenilin 1 (PS1) transgenic mice (AD model) received tDCS (0.2 mA, anode electrode placed on the left frontal skull, 20 min/d for two weeks) and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) activator nigericin. Behavior tests evaluated spatial learning, recognition memory, and spontaneous exploration abilities in mice. Histopathologic changes in the hippocampal cornu ammonis area 1 (CA1) region and Aβ1-42 deposition were observed using histologic staining and immunohistochemistry. Enzyme-linked immunosorbent assay was used to measure Aβ1-40 and Aβ1-42 expression. Classical microglia (M1)/alternative microglia (M2) polarization, inflammatory factors, and oxidative stress levels were assessed through immunofluorescence and kits. NLRP3 inflammasome indicators were detected by reverse transcription quantitative polymerase chain reaction and western blot.

RESULTS: After tDCS treatment, APP/PS1 mice exhibited shortened escape latency, increased platform crossings, and an elevated discrimination index. In the open field test, total movement distance and time spent in the center zone increased. The Aβ1-42/40 ratio in the mouse hippocampal CA1 region decreased by 20.8%, whereas neurons and Nissl bodies increased, indicating that tDCS improved cognitive function. tDCS reduced M1 polarization, increased M2 polarization, and reduced neuroinflammation and oxidative stress in the hippocampal CA1 region of APP/PS1 mice. Moreover, tDCS suppressed microglial NLRP3/caspase-1 pathway activation and Aβ deposition in APP/PS1 mice. NLRP3/caspase-1 pathway activation partially reversed effects of tDCS on APP/PS1 mice.

CONCLUSION: This study highlights the potential therapeutic value of tDCS in AD mice. It reveals that tDCS promotes hippocampal microglial M2 polarization and Aβ degradation to curtail NLRP3/caspase-1 inflammasome pathway activation, thereby improving cognitive function in APP/PS1 mice.},
}

@article {pmid42012542,
year = {2026},
author = {Tu, X and Fang, M and Yan, Y and Liu, Y and Yu, J and Chen, L and Zhang, L and Huang, C and Fan, S},
title = {The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.},
journal = {Biogerontology},
volume = {27},
number = {3},
pages = {},
pmid = {42012542},
issn = {1573-6768},
support = {24ZR1466100//Natural Science Foundation of Shanghai Municipality/ ; 25PJD123//Shanghai Magnolia Talent Plan of Shanghai - Pujiang Talents Program/ ; QNKJ2025007//Eastern Talent Program - Science and Technology Platform of Shanghai/ ; },
mesh = {*Histone Deacetylase 6/metabolism ; Animals ; *Triterpenes/pharmacology ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroprotective Agents/pharmacology ; Caenorhabditis elegans ; Humans ; *tau Proteins/metabolism/toxicity ; *Stress Granules/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; Caenorhabditis elegans Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by proteostasis collapse driven by amyloid-β (Aβ) plaques and tau tangles. Dysregulation of stress granule (SG) dynamics and aberrant histone deacetylase 6 (HDAC6) activity are emerging as pivotal pathogenic mechanisms promoting neurodegeneration. Here, we identify that Cucurbitacin B (CB), a natural triterpenoid, acts as a potent SG inducer that confers broad-spectrum neuroprotection. Mechanistically, we demonstrate a novel "recruit-and-sequester" model: CB promotes the assembly of HDAC6-recuited SGs, thereby physically sequestering HDAC6 and functionally inhibiting its deacetylase activity. In Caenorhabditis elegans (C. elegans) and mammalian cell models, CB treatment significantly alleviated Aβ oligomer-induced cytotoxicity and tau hyperphosphorylation. Notably, the neuroprotective efficacy of CB was abolished by the genetic knockdown of core SG components (gtbp-1/G3BP1, tiar-1/TIA1) or hda-6/HDAC6, confirming that its therapeutic action relies on the integrity of the HDAC6-SG. Our findings highlight the potential of modulating SG dynamics to spatially regulate HDAC6, offering a novel therapeutic strategy for AD.},
}

*Histone Deacetylase 6/metabolism
Animals
*Triterpenes/pharmacology
*Amyloid beta-Peptides/toxicity/metabolism
*Neuroprotective Agents/pharmacology
Caenorhabditis elegans
Humans
*tau Proteins/metabolism/toxicity
*Stress Granules/metabolism/drug effects
*Alzheimer Disease/metabolism/drug therapy
Caenorhabditis elegans Proteins/metabolism

@article {pmid42013009,
year = {2026},
author = {Botta, D and Bernetti, C and Hutuca, I and Ojeda Esparza, JF and Sveikata, L and Lovblad, KO and Kurz, FT},
title = {Beyond the Leak: Advanced MRI Assessment of the Blood-Brain Barrier in Neurodegeneration.},
journal = {Neuro-degenerative diseases},
volume = {},
number = {},
pages = {1-25},
doi = {10.1159/000552173},
pmid = {42013009},
issn = {1660-2862},
abstract = {The blood-brain barrier (BBB) is a specialized multicellular interface that maintains the CNS's tightly regulated microenvironment. BBB disruption is increasingly recognized as a key feature of neurodegeneration, documented across disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and cerebral small vessel disease (cSVD). While the extent to which BBB breakdown is a cause or consequence of neuronal pathology remains unclear, its pronounced presence in disease states suggests a significant contributory role in progression. Advances in MRI have revolutionized our ability to visualize and quantify these alterations in vivo. This review provides a neuroradiological overview of advanced MRI approaches and their specific biomarkers, specifically Dynamic Contrast-Enhanced MRI (DCE) with Ktrans and Arterial Spin Labeling (ASL) with kw, detailing disease-specific BBB signatures in major neurodegenerative disorders. Current technological strides, including ultra-high-field MRI and AI-assisted post-processing, are pushing the sensitivity needed to detect subtle BBB changes. Ultimately, with technical refinement and standardization, MRI methods are transitioning from research tools into candidate neurovascular biomarkers with growing potential for early diagnosis, treatment monitoring, and longitudinal follow-up, pending multicenter standardization and normative validation.},
}

@article {pmid42013076,
year = {2026},
author = {Jain, S and Tunc, EB and Grossberg, GT},
title = {Pharmacotherapeutic landscape for the management of agitation associated with Alzheimer's disease.},
journal = {Expert opinion on pharmacotherapy},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/14656566.2026.2662949},
pmid = {42013076},
issn = {1744-7666},
abstract = {INTRODUCTION: Agitation associated with Alzheimer's disease (AAD) is common, persistent, and strongly linked to caregiver burden, emergency care, and institutionalization. Pharmacologic options have historically been limited by modest efficacy and safety liabilities in the geriatric population, creating a major treatment gap.

AREAS COVERED: This narrative review summarizes established and emerging pharmacotherapies for AAD, emphasizing comparative efficacy, geriatric-relevant safety, and real-world feasibility. A literature search was conducted in PubMed/MEDLINE and ClinicalTrials.gov from database inception through 31 January 2026, prioritizing the most recent decade when applicable, and complemented these searches with hand searches of key trials, meta-analyses, guidelines, and publicly available regulatory or sponsor communications for late-stage programs. Evidence is synthesized qualitatively due to heterogeneity in definitions and outcomes. We discuss antipsychotics, serotonergic agents, drugs with negative trials, and pipeline approaches such as dextromethorphan-based combinations and adrenergic strategies.

EXPERT OPINION: The field is shifting from broad off-label prescribing toward phenotype-informed, trial-validated treatments. Brexpiprazole establishes regulatory feasibility, while dextromethorphan-based combinations, particularly AXS-05, appear promising, including signals for durability. Progress will depend on harmonized outcomes, longer-term safety data, and pragmatic trials that prioritize function, caregiver impact, and crisis prevention.},
}

@article {pmid42000569,
year = {2026},
author = {Schelter, BO and Shiells, H and Lo, S and Nazlee, N and Evans, E and Bentham, P and Gauthier, S and Zetterberg, H and Wilcock, GK and Froelich, L and Burns, A and MacSweeney, E and Ballard, C and Yu, JT and Choon, TS and Asvatourian, V and Muehlemann, N and Priel, J and Kook, K and Sullivan, T and Downie, D and Miller, S and Pringle, C and Storey, JMD and Baddeley, T and Harrington, CR and Staff, R and Sandu, AL and Hull, C and Stefanacci, R and Wischik, CM and , },
title = {Assessment of clinical and neuroimaging efficacy of treatment targeting tau pathology in mild cognitive impairment and mild to moderate Alzheimer's disease with hydromethylthionine mesylate using external control data.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100560},
doi = {10.1016/j.tjpad.2026.100560},
pmid = {42000569},
issn = {2426-0266},
abstract = {BACKGROUND: Hydromethylthionine mesylate (HMTM) targets tau pathology and also has tau-independent symptomatic activity. A traditional randomised placebo-controlled trial (RCT) was precluded by loss of blinding due to urinary colouration and therapeutic activity at the minimum dose required to maintain blinding.

OBJECTIVE: To evaluate the efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).

METHODS: Because a traditional RCT was not feasible without loss of blinding, we compared HMTM 16 mg/day in TRx-237-039 with propensity score matched true placebo controls from the FDA-sponsored Critical Path for AD (CPAD) database with the same inclusion/exclusion criteria (protocol TRx-237-080). We also compared HMTM 16 mg/day with matched natural history controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with a meta-analysis of placebo arms from trials in comparable populations in analyses specified prior to the 104-week database lock of TRx-237-039.

PARTICIPANTS: Propensity score matching yielded 127 pairs (HMTM n = 127; CPAD placebo n = 127) in the CPAD comparison, and 189 pairs in the ADNI comparison. A total of 218 receiving HMTM 16 mg/day were compared with meta-analytic controls (n = 1805-8567).

INTERVENTION: HMTM 16mg/day MEASUREMENTS: Primary outcomes in TRx-237-080 were change from baseline to 78 weeks in ADAS-Cog13 and whole brain volume (WBV). CDR-Sum of Boxes (CDR-SB) and CDR-Global were analysed at 104 weeks. ADAS-cog11 and WBV were analysed in ADNI comparisons, and ADAS-cog11, ADCS-ADL23, CDR-SB and WBV were analysed in meta-analytic comparisons.

RESULTS: Compared with matched CPAD placebo, HMTM 16 mg/day produced statistically significant differences in change on ADAS-Cog13 (p < 0.0001) and WBV at 78 (primary; p < 0.0001) and 104 weeks (p < 0.0001), and CDR-SB differed significantly overall (104-weeks; p < 0.001) and in MCI (p = 0.007). The odds of progressing to a more advanced CDR-Global stage were lower with HMTM (overall OR 0.31) and particularly in MCI (OR 0.15) versus CPAD placebo. Clinical and brain atrophy outcomes were similarly statistically significant in comparisons with ADNI case-matched natural history data and in meta-analytic comparisons.

CONCLUSION: Comparisons of HMTM treatment with CPAD, ADNI, and meta-analytic controls provide evidence consistent with clinical benefit HMTM. It has the potential to offer an accessible oral treatment option which could be delivered with minimal patient/physician burden.},
}

@article {pmid42001186,
year = {2026},
author = {Zheng, W and Geng, D and Wang, A and Li, Z and Liu, A and Chen, S and Wang, Q and Su, C and Yan, Z and Yin, Y and Xu, G},
title = {Gamma low field magnetic stimulation ameliorates pathophysiological damage and cognitive impairments in AD mice.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02052-1},
pmid = {42001186},
issn = {1758-9193},
support = {52277230//National Natural Science Foundation of China/ ; SJZZXB24006//Science and Technology Cooperation Special Project of Shijiazhuang/ ; 25292001D//Hebei Province Provincial Science and Technology Programme Project International Science and Technology Co-operation Special Project/ ; 2022YFC2402203//National Key R&D Program of China/ ; },
abstract = {BACKGROUND: The normal functioning of gamma rhythms is crucial for maintaining brain health, while their abnormalities are closely associated with various neurological disorders, particularly Alzheimer's disease. Gamma stimulation modalities including auditory, visual, electrical, and strong magnetic approaches have all demonstrated potential therapeutic effects for AD, with substantial research findings continuously emerging. However, 40 Hz gamma low field magnetic stimulation(gamma-LFMS) remains unexplored.

METHODS: To investigate this question, we applied pulsed magnetic fields with a magnetic field strength of 10 mT and frequency of 40 Hz (2 × 30 min/day) to 9-month-old APP/PS1 double transgenic AD model mice for 18 consecutive days, and evaluated changes in spatial memory capacity, hippocampal neural network characteristics, and amyloid protein 42 content in AD mice.

RESULTS: Gamma-LFMS significantly enhanced spatial memory performance in AD mice, increased theta-gamma phase-amplitude coupling and gamma band power in the hippocampal CA1 region, showed a trend toward desynchronization in low gamma, and effectively reduced hippocampal β-amyloid42 burden.

CONCLUSIONS: This study demonstrates for the first time that gamma-LFMS effectively ameliorates pathophysiological alterations and spatial memory deficits in AD mice. These findings address a critical knowledge gap regarding the effects of gamma-LFMS on AD pathology and provide a theoretical foundation for developing cost-effective home-based prevention and treatment devices applicable throughout the lifespan.},
}

@article {pmid42001306,
year = {2026},
author = {Thakur, A and Rana, M and Vanjani, S and Liou, KC and Taliyan, R and Nepali, K and Yang, CH},
title = {Multi-Targeting Ligands as Prospective Therapeutics for Alzheimer's Disease, a Prevalent Neurodegenerative Disorder: Mechanistic Insights, Emerging Targets and Drug Discovery Campaigns.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.70047},
pmid = {42001306},
issn = {1098-1128},
support = {NSTC 112-2320-B-038-018-MY3//National Science and Technology Council, Taiwan/ ; },
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive impairment, memory deterioration, and neuronal dysfunction. Its complex pathophysiology involves multiple interlinked processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, synaptic dysfunction, and cholinergic deficits. Current FDA-approved therapies provide only symptomatic relief and fail to halt disease progression, highlighting the urgent need for more effective treatment strategies. This review provides a comprehensive overview of the pathological mechanisms underlying AD and the emerging therapeutic targets for the design of tractable anti-AD scaffolds, namely, acetylcholinesterase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), glycogen synthase kinase-3β (GSK3β), dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), histone deacetylases (HDACs), and soluble epoxide hydrolase (sEH). Emphasis is placed on the paradigm shift from single-target therapies to multitarget-directed ligands (MTDLs), which are increasingly recognized as promising tools to tackle AD's multifactorial pathology. We also discuss recent advances in medicinal chemistry and structure-guided drug discovery campaigns aimed at developing pharmacologically optimized, BBB-penetrant MTDLs. By consolidating mechanistic insights with therapeutic innovation, this review aims to facilitate the development of next-generation therapeutics with enhanced efficacy and disease-modifying potential in AD.},
}

@article {pmid42002723,
year = {2026},
author = {Sukreet, S and Kim, EK and Petersen, M and Zhang, F and O'Bryant, SE and Rafii, MS and Rissman, RA},
title = {Precision medicine for Alzheimer's disease in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71398},
doi = {10.1002/alz.71398},
pmid = {42002723},
issn = {1552-5279},
support = {AG073979//NIH/NIA/ ; R61/R33AG066543//NIH/NIA/ ; },
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/drug therapy/diagnosis/blood/complications ; *Precision Medicine/methods ; Male ; Female ; Biomarkers/blood ; Middle Aged ; *Vitamin E/therapeutic use ; Proteomics ; Aged ; Neuropsychological Tests ; Support Vector Machine ; Extracellular Vesicles/metabolism ; },
abstract = {INTRODUCTION: Down syndrome (DS) exhibits a genetic form of Alzheimer's disease (AD). We used a blood-based proteomic algorithm to predict cognitive status, treatment responders, and change to vitamin E in DS adults from a completed clinical trial, "Vitamin E in Aged Persons with Down Syndrome," which originally showed no significant cognitive benefit using the primary endpoint cognition (Brief Praxis Test [BPT]).

METHODS: Plasma and extracellular vesicle (EV; astrocytic and neuronal) biomarkers were assayed at baseline and 36 months (n = 138 each). Cognitive response was measured using combined scores from the BPT, vocabulary, and behavior and function DS tests. Support vector machine (SVM) analyses predicted diagnostic and treatment responders and change accuracy.

RESULTS: SVM classified demented versus non-demented with up to 99% accuracy and predicted treatment response and changes with up to 100% accuracy in plasma and EV.

DISCUSSION: Our study supports blood-based screening and precision diagnostics for AD therapy in DS.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease/drug therapy/diagnosis/blood/complications
*Precision Medicine/methods
Male
Female
Biomarkers/blood
Middle Aged
*Vitamin E/therapeutic use
Proteomics
Aged
Neuropsychological Tests
Support Vector Machine
Extracellular Vesicles/metabolism

@article {pmid42004236,
year = {2026},
author = {Zhang, B and Zhang, M},
title = {Metabolic Regulatory Networks in Ferroptosis During Alzheimer's Disease, Mechanisms of Glial Cell Action, and Pathological Correlations with Neuritic Plaques.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {596584},
pmid = {42004236},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathological mechanism, which is still poorly understood. Ferroptosis is a type of non-apoptotic programmed cell death. Many recent studies have found that ferroptosis is closely related to the occurrence and development of AD. This article explains the main theoretical basis of ferroptosis in the pathological development of AD, and systematically analyzes the synergistic pathological network of multiple pathways caused by iron metabolism disorder, abnormal lipid peroxidation, and abnormal amino acid metabolism. This article mainly focuses on the dual regulation mechanism and molecular mechanism of microglia, astrocytes, and oligodendrocytes in the process of ferroptosis. This article studies the two-way relationship between neuritic plaques (NP) and ferroptosis, and the relationship between NP and dystrophic neurites, inflammatory response, and abnormal tau phosphorylation. Based on the existing research, we propose several unanswered questions and possible targeted research directions to provide a theoretical reference for the study of AD pathogenesis and the exploration of intervention strategies.},
}

@article {pmid42004570,
year = {2026},
author = {Shajahan, SR and Hein, ZM and Muhammad, H and Mustafa, MZ and Kumari, Y and Jazuli, I and Zulkapli, A and Shari, N and Nassir, CMNCM and Ramli, MDC},
title = {Stingless bee honey alleviates cognitive deficits and hippocampal neurodegeneration in an Alzheimer's model: Behavioural, neurochemical, and histological analyses.},
journal = {AIMS neuroscience},
volume = {13},
number = {1},
pages = {1-28},
pmid = {42004570},
issn = {2373-7972},
abstract = {Stingless bee honey (SBH), widely consumed in Southeast Asia, is traditionally valued for its medicinal and nutritional properties, particularly in promoting brain health. However, its neuroprotective potential against Alzheimer's disease (AD) remains underexplored. In this study, we investigated the therapeutic effects and safety of SBH in a rat model of AD. A total of sixty-three adult male Sprague-Dawley rats (180-200 g) were used: Fifteen were assigned to three toxicity groups (500, 750, 1000 mg/kg; n = 5) and forty-eight to six therapeutic groups (n = 8): Normal control, AD (AlCl3 + D-gal), AD + Donepezil (1.5 mg/kg), and three SBH-treated groups (500, 750, 1000 mg/kg). Alzheimer-like pathology was induced by aluminium chloride (150 mg/kg) and D-galactose (300 mg/kg), followed by 14 days of treatment. Toxicity was evaluated through liver and kidney histopathology, while behavioural performance was assessed using the Open Field Test and Morris Water Maze. Serum dopamine, serotonin, corticosterone, and acetylcholinesterase activity were quantified via ELISA, and hippocampal morphology was examined histologically. SBH administration produced no signs of systemic toxicity and significantly improved exploratory activity and spatial learning, with the most pronounced effects at 750 mg/kg. Biochemical assays showed reduced acetylcholinesterase and corticosterone levels alongside increased dopamine and serotonin concentrations. Histological analysis confirmed neuronal preservation and reduced hippocampal damage. Inclusion of Donepezil as a positive control enabled comparison with a standard pharmacological treatment. These findings demonstrated that SBH is a safe and promising natural therapeutic capable of alleviating cognitive deficits associated with AD.},
}

@article {pmid42005438,
year = {2026},
author = {Fleig, K and Haslinger, L and Dawczynski, C and Kolassa, IT},
title = {Omega-3 fatty acids in mental disorders: from neurobiological and metabolic mechanisms to therapeutic potential.},
journal = {Frontiers in nutrition},
volume = {13},
number = {},
pages = {1748196},
pmid = {42005438},
issn = {2296-861X},
abstract = {Nutritional psychiatry is an emerging field. Micro- and macro-nutrients play a role in energy metabolism and the regulation of inflammation; particularly, an insufficient dietary intake of omega-3 fatty acids and an imbalanced intake of omega-6/omega-3 fatty acids, with a shift toward increased inflammation, are of relevance for the pathophysiology of mental disorders. This review summarizes evidence on the role of omega-3 fatty acids in the pathophysiology of mental disorders (schizophrenia, affective and anxiety disorders, post-traumatic stress disorder, and eating disorders), neurodevelopmental disorders (attention-deficit/hyperactivity disorder and autism spectrum disorder) and neurodegenerative disorders (Alzheimer's disease) and explores potential treatment implications. In addition, the underlying neurobiological mechanisms through which omega-3 fatty acids might exert a protective effect are also discussed. Despite methodological variability and heterogeneous results, an increasing body of evidence suggests that omega-3 deficiency and altered fatty acid profiles are modifiable risk factors and potential biomarkers for mental disorders. The integration of omega-3 supplementation as an adjuvant to state-of-the-art therapy offers the potential for a low-risk intervention with meaningful clinical outcomes. However, clinical monitoring is recommended to avoid adverse effects and to adjust the dosage according to individual and disease-specific factors.},
}

@article {pmid42005580,
year = {2026},
author = {Imran, S and Patel, M and Noroozifar, M and Kerman, K},
title = {Recent advances towards BACE1 drug discovery and therapeutics design.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {42005580},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. A key feature of AD is the accumulation of amyloid beta (Aβ) peptides in the form of extracellular plaques. The amyloid cascade hypothesis suggests that the pathogenesis of AD is initiated by the cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Numerous therapeutic approaches have been pursued to target BACE1 due to its crucial role in AD. However, the complexity of AD and the localization of BACE1 in the brain have posed challenges, leading to the failure of clinical trials and, in some cases, even exacerbating disease progression. Specifically, the blood-brain barrier (BBB) prevents the entry of many molecules, making BACE1 a difficult target to approach. Recent advancements in BACE1 therapy have shifted the focus from traditional enzyme inhibitor-based therapeutics to modulators, antibody therapy, and gene therapy. These approaches offer several advantages, including the ability to efficiently cross the BBB and provide targeted treatment. In this review, we explore the latest developments in modulators, antibody therapy, and gene therapy targeting BACE1 to combat AD. These approaches offer a promising avenue to mitigate the progression of AD and provide a novel therapeutic strategy.},
}

@article {pmid42006102,
year = {2025},
author = {Manescu, MD and Catalin, B and Mateescu, VO and Rosu, GC and Boboc, IKS and Istrate-Ofiteru, AM and Liliac, IM and Busuioc, CJ and Pirici, D},
title = {AQP4 Drives Gliotic Changes in an APPPS1 Mouse Model of Alzheimer's Disease.},
journal = {Current health sciences journal},
volume = {51},
number = {4},
pages = {543-551},
pmid = {42006102},
issn = {2067-0656},
abstract = {Alzheimer's disease (AD) is the most common form of dementia, accounting for most of the cases, especially in individuals aged 65 and older. While the existence of genetic factors has helped us create animal models of AD that mimic APP and Ab overproduction, sporadic cases represent the bulk casuistry, and most probably their pathology is related to a loss of function towards the clearance of Ab rather than consecutive the overproduction of Ab alone. It is known that aquaporin 4 (AQP4) facilitation amplifies the perivascular Ab clearance route and decreases Ab deposits in animal models of AD, however it is now known how the glial component of the CNS responds to this treatment. We have aimed here to assess the glial response in a APPPS1 transgenic mouse model of AD, after one month of pharmacological facilitation or inhibition of AQP4. To this extent, we have utilized APPPS1 mice of 2 months of age, treated daily for 28 days with either TGN-020 AQP4 inhibitor or the TGN-073 AQP4 facilitator, and compared their GFAP expression in the brain with that of untreated APPPS1 and wild-type animals. Our image analysis of the GFAP immunohistochemical pattern, showed that AQP4 facilitation increases GFAP expression in the brains of APPPS1 animals, compared to untreated APPPS1 animals, but complexity-lacunarity morphological patterns resemble in fact those of wild-type animals, rather than that of the APPPS1 untreated animals, suggesting that this GFAP reactivity might represent a benefic amyloid-clearance astrocytic profile.},
}

@article {pmid42006158,
year = {2026},
author = {Wang, G and Duan, X and Ouyang, D and Zhou, J and Zhang, H and Ding, Y},
title = {Nose-to-brain delivery of donepezil within a small dose improves bioavailability and efficacy for Alzheimer's disease treatment.},
journal = {Asian journal of pharmaceutical sciences},
volume = {21},
number = {2},
pages = {101130},
pmid = {42006158},
issn = {2221-285X},
abstract = {Oral administration of donepezil (Don) is the first-line medication for Alzheimer's disease (AD); however, the dysphagia of elderly patients and severe gastrointestinal side effects substantially restrict administration compliance. Herein, we exploit a nose-to-brain pathway for Don administration to obtain smaller dosage but higher intracerebral bioavailability (BA), thereby achieving inhibition of acetylcholinesterase (AChE) activity and avoiding side effects. With respect to the intranasal administration design, a patient-friendly Don nasal spray without preservatives was developed. The administration of Don nasal spray demonstrated good nasal deposition and mucosa permeation ability comparable to that of the model drug propranolol. The mice intranasally administered Don at an equivalent oral dose (0.65 mg/kg) demonstrated rapid brain distribution (∼5 min) and long-lasting AChE inhibition effects (72 h). To obtain the optimal intranasal dose, a dose-descending study was conducted by cascading the oral dosage at a 1:3 ratio. The results demonstrated that intranasal administration of Don at 0.07 mg/kg resulted in intracerebral BA and AChE inhibition comparable to oral administration at 0.65 mg/kg, suggesting an 89% dose reduction. Compared with oral administration, anti-AD effectiveness was evaluated in AD model mice after 34-d- intranasal administration of Don, resulting in a shorter onset time, higher intracerebral drug concentration, and a longer duration of AChE inhibition (0.07 mg/kg). The nasal and systemic safety of intranasal administration of Don was confirmed in an allergic rhinitis mouse model after 4 weeks of intranasal administration. Thus, a small dose of Don exhibits improved intracerebral BA and AChE inhibition via intranasal administration, thereby offering better compliance and reducing side effects in AD treatment.},
}

@article {pmid41997807,
year = {2026},
author = {Washer, SJ and Frith, M and Cowan, E and Dempster, E and Mill, J and Farrow, SL},
title = {Epigenetic biomarkers in neurodegenerative diseases: from molecular signatures to therapeutic targets.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2026.03.004},
pmid = {41997807},
issn = {1878-108X},
abstract = {Collectively, neurodegenerative diseases impose an escalating global health burden, representing one of the leading causes of death and disability worldwide. Despite their growing prevalence, diagnosis and treatment remain major challenges, partly due to the absence of specific and reliable biomarkers for early detection, disease monitoring, and prognosis. Epigenetic biomarkers are emerging as promising clinical tools, although their potential in the context of neurodegenerative diseases is not yet fully realised. In this review, we provide an overview of advances in the understanding of DNA modifications and chromatin architecture in neurodegeneration, highlighting translational relevance for biomarker discovery and therapeutic development. Finally, building on insights from other diseases where epigenetic biomarkers are already applied, we discuss the key steps required to enable implementation in neurodegenerative diseases.},
}

@article {pmid41998449,
year = {2026},
author = {Chauhan, P and Wadhwa, K and Singh, G},
title = {Geraniol and Z-guggulsterone co-treatment attenuates Alzheimer's disease in adult zebrafish by targeting oxidative damage, neuroinflammation, mitochondrial stress, and synaptic dysfunction.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41998449},
issn = {1568-5608},
abstract = {Given the multifactorial pathogenesis of Alzheimer's disease (AD) and the limited efficacy of single-target drug therapy, there is a growing scientific need for combination regimens to concurrently target various AD-associated cascades. Currently, plant-derived phytoconstituents, with their intrinsic multi-target properties, represent a promising component for combination therapy, offering translational potential with enhanced neuroprotection. In this avenue, the current study aimed to explore the combined neuroprotective effects of geraniol (a monoterpenoid alcohol) and Z-guggulsterone (a phytosterol) in streptozotocin (STZ)-induced AD model of adult zebrafish (4-6 months old). Following intracerebroventricular STZ injection, zebrafish were treated with geraniol and Z-guggulsterone per se and in combination for 28 consecutive days. On day 27, a novel tank diving test and a light/dark preference test were performed to evaluate locomotive and cognitive impairments. Afterwards, the fish were evaluated for numerous blood parameters, including blood glucose and serum cholesterol levels, followed by biochemical assessment of oxidative stress markers, mitochondrial complexes, neuroinflammatory cytokines, and neurotransmitter levels. Results demonstrated that co-therapy of geraniol and Z-guggulsterone significantly ameliorated cognitive deficits, reduced anxiety-like behaviours, impeded acetylcholinesterase activity, regulated neurotransmitter levels (glutamate and acetylcholine), mitigated oxidative stress markers, and prevented mitochondrial dysfunction, compared to monotherapies. Additionally, downregulation of TNF-α was also observed, affirming suppression of detrimental neuroinflammatory processes. Collectively, these findings support the neuroprotective potential of geraniol and Z-guggulsterone co-therapy in the zebrafish model of AD; however, future research is warranted to explore the potential clinical application of this combination therapy in AD.},
}

@article {pmid42000003,
year = {2026},
author = {Zou, F and Ren, X and Huo, G and Peng, L and Sun, C},
title = {Tianwang Buxin Pill improves cognitive function in APP/PS1 mice by reducing neuronal damage and regulating synaptic plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121683},
doi = {10.1016/j.jep.2026.121683},
pmid = {42000003},
issn = {1872-7573},
abstract = {As a progressive neurological degenerative disorder, Alzheimer's disease (AD) remains a significant concern, with the lack of effective cures burdening healthcare resources and posing ongoing obstacles for scientific research in neuroscience. Tianwang Buxin Pills (TWBXP) is a traditional Chinese medicinal formula long employed for treating amnesia and cognitive decline, and has shown promising potential in AD treatment. Nevertheless, the detailed mechanisms responsible for these effects warrant further investigation.

AIM OF THE STUDY: This study seeks to systematically evaluate the impact of TWBXP on cognition, neuronal damage, and synaptic plasticity in AD mice, while clarifying its underlying therapeutic mechanisms.

MATERIALS AND METHODS: HPLC-UV was employed to ensure the quality of TWBXP. APP/PS1 mice were administered TWBXP (0.43, 0.85, 1.70 g/kg) for 8 weeks, and cognitive performance was assessed using behavioral tests. AD-related pathology was evaluated by Immunohistochemistry (IHC), Western blotting, ELISA, Transmission electron microscopy (TEM), and Immunofluorescence (IF). The integration of Network Pharmacology and Proteomics was conducted for the exploration of potential mechanisms.

RESULTS: TWBXP markedly improved cognitive performance and reduced cerebral Aβ burden. It promoted microglial polarization toward an M2 phenotype, dampened neuroinflammation, and enhanced microglia-associated Aβ clearance. TWBXP also exerted marked neuroprotective and synaptic protective effects by increasing NeuN, MAP2, and MBP levels, restoring synaptic proteins (PSD95, SYP) and neurotrophic factors (BDNF, NGF), reducing neuronal loss and functional impairment, and improving synaptic plasticity. Such effects might be associated with the enhanced activity of the cAMP/PKA/NR2B/CaMKⅡ signaling axis.

CONCLUSIONS: TWBXP significantly ameliorated cognitive impairment and AD-related pathological changes in APP/PS1 mice, accompanied by improvements in neuronal injury and synaptic plasticity. Its therapeutic effects may be associated with the regulation of microglial function and the cAMP/PKA/NR2B/CaMKII signaling axis.},
}

@article {pmid42000213,
year = {2026},
author = {Littmann-Crites, V and Marrache, AM and Tan, C and Nightingale, N and Neish, CS and Therrien, F and Ismail, Z},
title = {Treatment patterns of agitation associated with Alzheimer's dementia (AAD) patients in Canada.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100209},
doi = {10.1016/j.inpsyc.2026.100209},
pmid = {42000213},
issn = {1741-203X},
abstract = {OBJECTIVES: Explore treatment patterns of Canadian patients with AAD to understand variability in clinical management.

DESIGN: This retrospective study used public claims data from Ontario and New Brunswick in IQVIA databases.

SETTING: Inferred patients with AAD were identified through claims for cognitive enhancers and medications used off-label to treat AAD, i.e., antipsychotics (AP), anticonvulsants (AC), antidepressants (ADT), benzodiazepines (benzo).

PARTICIPANTS: Patients (≥55 years) were identified between 2011-2018, indexed on their first AP/AC/AD/benzo and followed until the earlier of their fourth line (4L) of therapy or September 30, 2023. An all-history lookback to 2003 was used to ensure no prior claims for these therapies.

MEASUREMENTS: Descriptive analyses explored treatment utilization patterns.

RESULTS: 23,732 patients with AAD were identified, mostly from Ontario (98.7%). Patients with AAD tended to move to long-term care, with these increasing with more treatment trials from 24% (1 L therapy) to 54% (4 L therapy). Patients received between 500 and 2000 unique combinations across therapy lines. Citalopram, escitalopram, gabapentin, lorazepam, mirtazapine, pregabalin, quetiapine, risperidone, sertraline, and trazodone ranked in the top 10 therapies. Risperidone accounted for 7.2% of claims and ranked as the 6th most common 1 L therapy. Although trazodone remained the most common therapy for patients with AAD, it had one of the lowest persistence rates. Most patients remained on their 3 L - 4 L therapy, and ≥ 80% were adherent across all therapy lines. Average daily doses were lower than those described in the product monographs.

CONCLUSIONS: AAD treatment varies widely, underscoring the need for approved treatments and enhanced clinical education.

CLINICAL TRIAL NUMBER: Not applicable.},
}

@article {pmid41808074,
year = {2026},
author = {Lu, H and Chen, S and Tang, Y and He, W and Xia, S and Wu, Y},
title = {Sex differences in the associations between illness representations and behavioral intentions to seek early Alzheimer's detection in Chinese older adults.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {41808074},
issn = {1471-2318},
support = {Y202353191//General Scientific Research Project of the Zhejiang Provincial Department of Education/ ; 82271482//National Natural Science Foundation of China/ ; 2023ZY1018//Department of Science and Technology of Zhejiang Province/ ; OJQDSP2022013//Oujiang Laboratory/ ; },
abstract = {OBJECTIVES: Alzheimer’s disease (AD) is the most common form of dementia in older adults with no cure. Early detection and intervention are critical for improving patient outcomes. However, behavioral intentions to seek early detection of AD (BI-SEDAD) remain low. Illness representations, referring to individuals’ beliefs about illness, may influence BI-SEDAD. This study aimed to investigate the associations between illness representations and BI-SEDAD among Chinese older adults, and potential sex differences in these associations.

METHODS: A survey was conducted among 509 Chinese older adults. Participants completed the assessment of BI-SEDAD and illness representations of AD. Moderation analyses were conducted using SPSS PROCESS.

RESULTS: Consequences (β = 0.26), timeline (β = 0.23), illness identity (β = 0.22), illness coherence (β = 0.21), illness concern (β = 0.22), and emotional representations (β = 0.24) were positively associated with BI-SEDAD, whereas treatment control was negatively associated (β = − 0.10). Moreover, sex significantly moderated the associations between BI-SEDAD and consequences (β = − 0.20), treatment control (β = 0.21), illness identity (β = − 0.17), illness coherence (β = − 0.25), and illness concern (β = − 0.26). Specifically, the associations between BI-SEDAD and consequences, illness identity, illness coherence, and illness concern were stronger in males than in females. The association between BI-SEDAD and treatment control was significant only in males.

CONCLUSIONS: Illness representations are important predictors of BI-SEDAD, with notable sex differences. Tailored interventions that address key beliefs and consider sex differences may promote early detection in older populations.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-026-07288-y.},
}

@article {pmid41870777,
year = {2026},
author = {Mostafa, RE and Asaad, GF},
title = {Bridging the gaps in alzheimer's disease: a comprehensive review of current and emerging therapies.},
journal = {Inflammopharmacology},
volume = {34},
number = {4},
pages = {2219-2241},
pmid = {41870777},
issn = {1568-5608},
abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide, accounting for 60–80% of dementia cases. It is characterized by gradual cognitive decline, neuronal loss, and pathological hallmarks, including amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein. This review provides a comprehensive overview of AD, emphasizing its etiology, molecular mechanisms, risk factors, and current therapeutic strategies. Multiple hypotheses, including the amyloid cascade, tau, cholinergic, vascular, and neuroinflammatory theories, are discussed to elucidate disease pathogenesis. Genetic mutations in the APP, PSEN1, and PSEN2 genes, along with environmental and lifestyle factors, are shown to influence disease onset and progression. The treatment landscape is rapidly evolving from traditional symptomatic therapies, such as cholinesterase inhibitors and NMDA receptor antagonists, to emerging disease-modifying agents targeting amyloid, tau, and neuroinflammation. Novel approaches, including glutaminyl cyclase inhibitors, PDE inhibitors, serotonin receptor modulators, and metabolic therapies, offer new hope for altering disease progression. Non-pharmacological interventions, such as diet, exercise, and lifestyle modifications, also play a key preventive role. Despite ongoing challenges, advancements in biomarker research, neuroimaging, and precision medicine are improving early detection and individualized treatment strategies. Continuous innovation in pharmacotherapy and diagnostics promises to reshape the future of AD management and enhance patients’ quality of life. The current review focuses on bridging the gaps in AD’s current and emerging Therapies.},
}

@article {pmid41991715,
year = {2026},
author = {Wei, P and Zhu, T and Hashimoto, K and Jia, M and Yang, JJ},
title = {Exploring the lung-brain axis in perioperative neurocognitive disorders: a potential therapeutic target.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41991715},
issn = {1476-5578},
support = {82571352//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82571374//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades.},
}

@article {pmid41991786,
year = {2026},
author = {Flores-Melivilu, D and Carrazana, E and García, N and Alarcón, S and Caru-Ruiz, M and Chacón-Fuentes, M and Santos, N and Ahumada, M and Nova, E and Diaz-Espinoza, R and Sanhueza, M and Hormazábal, E and Salvadores, N},
title = {Aristotelia chilensis Fruit Extracts Exhibit Neuroprotective Properties Against Alzheimer's Disease Related Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41991786},
issn = {1559-1182},
mesh = {*Plant Extracts/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Fruit/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Animals ; Cell Survival/drug effects ; Humans ; Glutamic Acid/toxicity ; Acetylcholinesterase/metabolism ; Neurons/drug effects/metabolism/pathology ; *Elaeocarpaceae/chemistry ; },
abstract = {Aristotelia chilensis (maqui) extracts have garnered interest for their potential bioactivity, yet their specific effects on Alzheimer's disease (AD) pathology remain understudied. This study evaluated the neuroprotective properties of white and black maqui fruit extracts against glutamate-induced excitotoxicity and β-amyloid (Aβ) fibrillogenesis in vitro. Pre-treatment with maqui extracts significantly mitigated glutamate toxicity, increasing cell viability from 26.8% in glutamate-treated cells to 49.9% and 48.8% for white and black maqui, respectively. Furthermore, the extracts reduced Fluorojade C-positive degenerating neurons by up to 86.4% compared to the glutamate control. The extracts also exhibited potent anti-fibrillogenic activity, suppressing Aβ fibril formation by up to 77% in the ThT assay. Electron microscopy confirmed this inhibitory effect by showing a reduction in fibrillar structures. In contrast, neither extract inhibited acetylcholinesterase nor butyrylcholinesterase activity. Together, these results indicate that maqui fruits contain compounds capable of modulating key pathological features of AD in vitro, supporting their potential for further investigation.},
}

*Plant Extracts/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/metabolism
*Fruit/chemistry
*Neuroprotective Agents/pharmacology/therapeutic use
Amyloid beta-Peptides/metabolism
Animals
Cell Survival/drug effects
Humans
Glutamic Acid/toxicity
Acetylcholinesterase/metabolism
Neurons/drug effects/metabolism/pathology
*Elaeocarpaceae/chemistry

@article {pmid41992414,
year = {2026},
author = {Micocci, S and Parisotto, S and Alberti, D and Lanfranco, A and Bitonto, V and Renzi, P and Salmi, M and Bello, FD and Pagano, K and Ragona, L and Protti, N and Deagostino, A and Geninatti Crich, S},
title = {Carboranyl-Curcuminoids for the Neutron Capture-Based Treatment of Amyloid Aggregates in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e21701},
doi = {10.1002/advs.202521701},
pmid = {41992414},
issn = {2198-3844},
support = {D13C22003520001//Dipartimenti di Eccellenza/ ; D13C25000220007)//Compagnia di San Paolo/ ; 964934//H2020 Future and Emerging Technologies/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. The aggregation of amyloid-beta (Aβ) peptides into oligomers and fibrils is central to its pathogenesis. While oligomers represent the most neurotoxic species, larger aggregates serve as reservoirs, maintaining pathological Aβ levels. To our knowledge, this study is the first to investigate Boron Neutron Capture Therapy (BNCT) as a method to selectively destabilize Aβ aggregates. This is achieved by inducing structural modifications in the Aβ peptide, aiming to convert fibrils into innocuous species. The approach utilizes [10]B-enriched monocarbonyl analogs of curcumin (BMACs), a novel molecule that binds to Aβ fibrils and enables the site-specific release of high-linear-energy-transfer (LET) α particles and lithium ions upon neutron exposure. In vitro, Aβ aggregates were characterized using FESEM and Thioflavin T staining. The binding affinities of BMACs were determined through competition assays, with inhibition constants calculated using the Cheng-Prusoff equation. Post-irradiation analysis by [1]H-NMR and mass spectrometry demonstrated selective oxidation of histidine residues, a chemical modification capable of inducing fibril destabilization. This study provides proof of concept that not only offers future perspectives for Alzheimer's treatment but also enhances the understanding of radiation effects on proteins, particularly within the context of amyloidosis.},
}

@article {pmid41992726,
year = {2026},
author = {Evers, A and Watson, K and Abbasi, F and Haque, K and Verma, A and Eitan, E and Rasgon, N},
title = {Insights from changes in NDEV biomarkers of metabolism: Effects of PPARγ and GLP1 receptor agonists on brain metabolism.},
journal = {The Journal of clinical endocrinology and metabolism},
volume = {},
number = {},
pages = {},
doi = {10.1210/clinem/dgag176},
pmid = {41992726},
issn = {1945-7197},
abstract = {BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD).

METHODS: We analyzed biological samples from two cohorts of clinical trial participants: 1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and 2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups.

RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all p ≤ 0.02) compared to placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; p = 0.04 and p = 0.025, respectively) compared to placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test.

DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.},
}

@article {pmid41993246,
year = {2026},
author = {Pattanashetty, SG and Serrano, PA and Rockwell, P and Xie, L and Figueiredo-Pereira, ME},
title = {Terazosin drives sex-dependent adrenergic-bioenergetic reprogramming to restore network function in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716175},
pmid = {41993246},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) has long been defined by amyloid-β plaques and hyperphosphorylated tau, yet disease-modifying therapies remain critically limited. Growing evidence reframes AD as a system-level failure driven by early dysregulation of synaptic, metabolic, and neuroimmune pathways, preceding overt protein aggregation and originating in selectively vulnerable circuits, including the locus coeruleus (LC)-hippocampal noradrenergic axis. This complexity underscores the need for therapeutic strategies that engage the disease at a network level, early in its trajectory. To this end, using a machine learning-based systems pharmacology framework for drug repurposing applied to human AD transcriptomic datasets, we identified terazosin (TZ) as a candidate predicted to reverse AD-associated molecular signatures. TZ is an FDA-approved α1-adrenergic receptor antagonist and phosphoglycerate kinase-1 activator. It was administered chronically via the diet (0.5 mg/kg bw/day) to male and female TgF344-AD rats and wild-type littermates from 5 to 11 months of age, preceding overt pathology. Bulk hippocampal RNA sequencing revealed sex-specific transcriptional remodeling in transgenic rats, strongly conserved with human AD datasets. Male TgF344-AD rats exhibited suppression of synaptic and transcriptional maintenance pathways with concurrent activation of metabolic, proteostatic, extracellular matrix, and vascular stress responses; females showed suppression of survival and vascular structural signaling alongside heightened DAM-like immune activation, amyloid-associated stress, and cell death programs. TZ reversed these signatures in a sex-dependent manner: males showed enhanced immune surveillance and reduced proteostasis burden, while females showed reinforcement of synaptic, survival, and metabolic pathways. TgF344-AD rats displayed selective LC-derived hippocampal noradrenergic axonopathy without global neuronal loss. TZ preserved fiber integrity preferentially in females and partially reversed LC vulnerability-associated transcriptional signatures in both sexes. TZ also reduced amyloid-β plaque burden in both sexes, attenuated hyperphosphorylated tau exclusively in females, and induced microglial morphological shifts in males. Finally, TZ restored wild-type spatial learning in transgenic animals, with females appearing to derive the greater cognitive benefit. Together, these findings demonstrate that TZ induced systems-level reprogramming of AD-relevant molecular pathways and preserved vulnerable noradrenergic circuitry in a sex-dependent manner. Moreover, TZ rescued spatial cognition in transgenic rats, with cognitive gains seemingly more pronounced in females. These results support adrenergic-bioenergetic modulation as a translational strategy for early-stage AD and underscore the necessity of sex as a biological variable in disease-modifying treatment development.},
}

@article {pmid41993389,
year = {2026},
author = {Negida, A and , },
title = {Alpha-synuclein co-pathology amplifies amyloid-driven tau accumulation across Braak stages without modifying tau-cognition associations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.31.713304},
pmid = {41993389},
issn = {2692-8205},
abstract = {INTRODUCTION: Alpha-synuclein (αSyn) is the most common co-pathology in Alzheimer's disease (AD), yet its role within the amyloid-tau-neurodegeneration (ATN) cascade is unknown.

METHODS: We analyzed 636 ADNI participants with CSF αSyn seed amplification assay, amyloid PET, regional tau PET (Braak I-VI), structural MRI, and cognitive composites. Interaction models tested whether αSyn modifies the amyloid-tau and tau-cognition associations.

RESULTS: αSyn positivity (19.0%) amplified the amyloid-tau association across all Braak stages (meta-temporal interaction β = 0.258, 95% CI 0.104-0.411, p = 0.001), with strongest effects in Braak III-IV. αSyn did not modify tau-cognition associations in any domain (all interaction p > 0.18).

DISCUSSION: αSyn co-pathology selectively amplifies amyloid-driven tau propagation without modifying downstream tau-cognition relationships, identifying a node-specific effect within the ATN cascade with implications for patient stratification.

RESEARCH IN CONTEXT: Systematic review: We searched PubMed for studies combining α-synuclein seed amplification assays with amyloid and tau PET in Alzheimer's disease. One recent study (Franzmeier et al., 2025) demonstrated that α-synuclein co-pathology accelerates amyloid-driven tau accumulation. No study has examined whether α-synuclein modifies the downstream tau-cognition relationship or assessed regional tau specificity across all Braak stages.Interpretation: In 636 ADNI participants, α-synuclein co-pathology amplified the amyloid-tau association across all Braak stages but did not modify tau-cognition relationships. This dissociation identifies α-synuclein as a node-specific modifier of the ATN cascade, acting at the amyloid-to-tau transition.Future directions: Longitudinal studies with serial tau PET and α-synuclein SAA are needed to establish temporality. Clinical trials should evaluate whether α-synuclein stratification improves prediction of anti-amyloid treatment response.},
}

@article {pmid41993400,
year = {2026},
author = {Kammala, AK and Tatiparthy, M and Sreenivasmurthy, SGS and Garza, KH and Budhwani, S and Richardson, L and Menon, R and Krishnan, B},
title = {Exofection as a Therapeutic Modality: Restoring P-gp Activity via Trophoblast-Derived EV in Neuroinflammatory Disorders.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716001},
pmid = {41993400},
issn = {2692-8205},
abstract = {BACKGROUND: P-glycoprotein (P-gp/ABCB1) is a key efflux transporter that maintains barrier integrity by clearing xenobiotics and toxic metabolites. At the feto-maternal interface, trophoblast-derived extracellular vesicles (CTC-EVs) naturally and transiently transfer functional P-gp to maternal decidual cells, restoring lost and or reduced P-gp function (exofection) to sustain pregnancy homeostasis. A similar loss of P-gp at the blood brain barrier (BBB) contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer's disease. We investigated whether CTC-EV-mediated exofection could restore P-gp function in human brain endothelial cells (hBECs) and enhance Aβ clearance under inflammatory and neurodegenerative conditions.

METHODS: CTC-EVs were isolated and characterized by nanoparticle tracking analysis and western blotting for P-gp and EV markers. Transcriptomic profiling of CTC-EVs identified enrichment of transporter-related genes, including solute carriers and ABC transporters, along with inflammatory mediators. Network analysis revealed coordinated modules linking EV cargo to transporter regulation, endocytosis/trafficking pathways, and inflammatory remodeling processes converging on BBB efflux activity. hBECs were exposed to LPS (500 ng/mL, 48 h) with or without CTC-EVs. P-gp expression was assessed by immunofluorescence (mean fluorescence intensity, MFI) and western blotting, while functional efflux was measured using Calcein-AM assays. Aβ oligomer transport was evaluated using a transwell hBEC model. In vivo, 3xTg-AD mice received intravenous CTC-EVs (1×10L/day for 5 days), followed by assessment of P-gp expression, Aβ burden, and neuroinflammatory markers. Pharmacokinetic studies in P-gp knockout mice were conducted to confirm functional transporter recovery.

RESULTS: LPS exposure significantly reduced P-gp expression in hBECs (41.3% decrease in MFI, p=0.0084), which was restored by CTC-EVs (46.7% increase vs. LPS, p=0.0121). Exofection increased P-gp by a 2.1-fold following EV treatment as determined by western blot. Functional assays demonstrated enhanced efflux, with a 38.5% reduction in intracellular Calcein fluorescence (p<0.001). Network-informed mechanisms supported coordinated regulation of transporter and trafficking pathways. CTC-EVs improved Aβ transport across inflamed hBEC monolayers. In vivo, EV-treated 3xTg-AD mice exhibited increased P-gp expression in the frontal cortex (38.6%) and hippocampus (42.1%), reduced Aβ plaque burden (27.9%), and decreased inflammatory markers (IL-1β and TNF-α, p<0.05). In P-gp knockout mice, EVs reduced brain drug accumulation by 22.4% (p=0.032), confirming restoration of transporter function.

CONCLUSION: CTC derived EVs are natural carriers of functional transporter proteins and restore efflux capacity in compromised endothelial barriers. Integration of transcriptomic and network analyses highlights coordinated regulation of transporter, trafficking, and inflammatory pathways underlying exofection. This reproductive biology inspired strategy offers a promising therapeutic approach for enhancing Aβ clearance and mitigating neuroinflammation in Alzheimer's disease.},
}

@article {pmid41993974,
year = {2026},
author = {Han, H and Hou, L and Lu, J and Sun, H and Ning, W and Liang, Y and Gu, Y and Yin, H and Gao, Q},
title = {The intellectual landscape of cognitive impairment in type 2 diabetes: knowledge structure, research focuses and rising trends.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1809245},
pmid = {41993974},
issn = {1664-2392},
mesh = {*Diabetes Mellitus, Type 2/complications/psychology ; Humans ; *Cognitive Dysfunction/etiology/epidemiology/psychology ; Bibliometrics ; *Biomedical Research/trends ; },
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent worldwide, with cognitive dysfunction emerging as a significant complication. Despite extensive research into its pathological mechanisms and clinical management, the knowledge structure, research priorities, and developmental trends within this field remain unsystematically integrated.

METHODS: To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on type 2 diabetes mellitus (T2DM) and cognitive dysfunction were primarily retrieved from the Web of Science Core Collection (WOSCC) database from its inception to November 5, 2025. Searches were also conducted in PubMed and Scopus to verify completeness, but the final dataset was derived mainly from WOSCC due to its optimal export format for CiteSpace (plain text with full records and cited references) and high overlap after deduplication. Employing bibliometric methods and tools such as CiteSpace (version 6.4 Advanced) and SCImago Graphica (version 1.0.39), we conducted visual analyses of publication trends, country/region collaboration, institutional distribution, author contributions, journal impact, co-cited references, and keywords.

RESULTS: A total of 1,752 publications were included. Annual publication volume exhibited a marked upward trend, accelerating particularly after 2018. China, the United States, and the United Kingdom were the primary contributing nations, with close inter-institutional collaboration. High-frequency keywords included 'type 2 diabetes mellitus', 'Alzheimer's disease', and 'cognitive impairment'. Research focus has shifted from early risk factors to microscopic levels, including neuroimaging, gut microbiota, and molecular mechanisms.

CONCLUSION: Research on cognitive dysfunction in T2DM exhibits multidisciplinary characteristics, balancing fundamental research with clinical translation. Future efforts should enhance multidimensional integration of mechanism studies to advance early screening and personalised treatment strategies.},
}

*Diabetes Mellitus, Type 2/complications/psychology
Humans
*Cognitive Dysfunction/etiology/epidemiology/psychology
Bibliometrics
*Biomedical Research/trends

@article {pmid41994122,
year = {2026},
author = {Iglesias, JE and Johnson, IP and Williams-Ramirez, J and Zemlyanker, D and Tian, L and Gopinath, K and Olchanyi, M and Farnan, AD and Demopoulos, A and Rosen, MS and Sheth, KN and de Havenon, A and Kimberly, WT and Sorby-Adams, A},
title = {On the accuracy of image registration in portable low-field 3D brain MRI.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8255109/v1},
pmid = {41994122},
issn = {2693-5015},
abstract = {Portable low-field MRI offers an affordable and mobile alternative to conventional high-field scanners, enabling imaging in point-of-care and resource-limited settings. However, its lower signal-to-noise ratio, reduced resolution, and acquisition artifacts raise concerns about the accuracy of standard image registration methods. Reliable registration is critical for a wide range of emerging applications, including frequent brain monitoring, assessment of neurodegenerative disease progression, and evaluation of treatment effects such as those of Alzheimer's therapeutics. In this work, we systematically evaluated state-of-the-art registration approaches on simulated low-field scans (obtained by downsampling high-field images) and on real low-field brain MRI data. We compared three representative approaches: classical optimization (NiftyReg), learning-based registration (SynthMorph), and synthesis-based registration (SynthSR+NiftyReg). Using downsampled high-field scans, all methods performed well, achieving high Dice scores and smooth deformation fields, indicating that reduced resolution alone does not hinder registration. In contrast, real low-field data exhibited lower accuracy, primarily due to geometric distortion and other acquisition-specific artifacts. Among the tested approaches, the synthesis-based pipeline achieved the most robust performance across subjects and modalities. Overall, existing algorithms can accommodate resolution limitations, however, future methods could further enhance coregistration by explicitly addressing the distortions present in low-field MRI scans.},
}

@article {pmid41994275,
year = {2026},
author = {Yu, T and Yu, Y and Zhao, J and Li, H and Lu, H and Li, Y and Peng, Y and Wang, S and Wei, W and Cheng, X},
title = {Qifuyin improves physiological frailty by regulating the intestinal flora in 3xTg-AD mice.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1753643},
pmid = {41994275},
issn = {1664-302X},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is often accompanied by motor dysfunction, impaired limb strength, and gut microbiota disturbances. This study aimed to evaluate the effects of Qifuyin (QFY), a traditional Chinese medicine formula, on motor deficits, limb strength, aging, and gut microbiota composition in 3xTg-AD mice, a widely used model of AD.

METHODS: Male and female 3xTg-AD mice were administered QFY at low, medium, or high doses. Motor function was assessed using grip strength and rotarod tests. Aging was evaluated through aging scores. Gut microbiota composition was analyzed at the phylum, family, genus, and species levels. Functional profiling of microbiota was performed using KEGG, eggNOG, and carbohydrate-active enzyme (CAZyme) databases. Pearson correlation analyses were conducted to explore relationships between microbiota composition and motor performance.

RESULTS: QFY treatment significantly improved both absolute and normalized grip strength in male and female 3xTg-AD mice. Similarly, motor coordination, as assessed by latency to fall on the rotarod, was significantly enhanced in the groups of QFY. Aging scores were significantly reduced after the treatment of QFY. Microbiome analysis revealed that QFY treatment restored species diversity and improved the overall composition of gut microbiota, with significant increases in Muribaculaceae and decreases in Alcaligenaceae, Rhodanobacteraceae, and Spirochaetaceae. Principal component analysis (PCA) indicated that the gut microbiota composition of the QFY group resembled that of the control (Con) group. Functional analyses showed that treatment of QFY restored microbial pathways related to metabolism and genetic information processing, with significant correlations between microbial alterations and improved motor outcomes. Additionally, QFY modulated the abundance of key carbohydrate-active enzymes, including GH43 and GH35, which were positively correlated with grip strength and rotarod performance.

CONCLUSION: Qifuyin improves motor function, reduces aging-related deficits, and restores gut microbiota homeostasis in 3xTg-AD mice. These findings suggest that QFY may offer therapeutic potential for addressing frailty and motor dysfunction in AD, in association with alterations in gut microbiota composition and predicted microbial functions.},
}

@article {pmid41994888,
year = {2026},
author = {Yang, Z and Sang, P and Han, Y and Jiang, B and Kong, L and Zhou, X},
title = {Personalized treatment design in the context of functional confounding.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag056},
pmid = {41994888},
issn = {1541-0420},
support = {12171242//National Natural Science Foundation of China/ ; 72342019//National Natural Science Foundation of China/ ; },
mesh = {Humans ; Alzheimer Disease/therapy/diagnostic imaging ; *Precision Medicine/methods/statistics & numerical data ; Computer Simulation ; Neuroimaging ; Machine Learning ; Disease Progression ; Confounding Factors, Epidemiologic ; Biometry/methods ; },
abstract = {One of the primary goals of individualized treatment rule (ITR) methodology is to identify optimal decision rules using clinical predictors. While functional data has become increasingly available in biomedical research, there has been limited work on incorporating functional data into ITR estimation, particularly in observational studies. In this paper, we propose a novel approach that integrates outcome-weighted learning (OWL) with reproducing kernel Hilbert space to determine optimal treatment regimes involving functional data. Furthermore, to address the issue of data piling, we employ the distance-weighted discrimination classifier instead of traditional support vector machines. We establish the theoretical consistency of the decision functional estimator with its risk bound. Extensive simulations and the analysis of the Alzheimer's Disease Neuroimaging Initiative dataset demonstrate the superior performance of our method compared to existing OWL approaches. The results highlight critical factors in Alzheimer's Disease progression and reveal limitations of the original OWL method in this context.},
}

Humans
Alzheimer Disease/therapy/diagnostic imaging
*Precision Medicine/methods/statistics & numerical data
Computer Simulation
Neuroimaging
Machine Learning
Disease Progression
Confounding Factors, Epidemiologic
Biometry/methods

@article {pmid41996008,
year = {2026},
author = {Woźniak-Mitał, J and Rasmus, P and Strombek-Milczarek, M and Kaźmierski, J},
title = {The Impact of Transcranial Direct Stimulation Therapy Combined with Intranasal Near-Infrared Stimulation on Cognitive Performance in Patients with Mild Cognitive Impairment and Alzheimer's Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Study.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41996008},
issn = {2193-8253},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are progressive neurodegenerative conditions with limited therapeutic options. Neuromodulation techniques such as transcranial direct current stimulation (tDCS) and photobiomodulation (PBM) have shown promise in improving cognitive function, but their combined effects remain underexplored.

METHODS: In a pilot randomized, double-blind, placebo-controlled trial, 33 participants were assigned to either active or sham stimulation groups. The intervention consisted of 50 sessions over 10 weeks, with tDCS (2 mA, F3-F4 montage) and intranasal near-infrared stimulation (iNIRS) (850 nm, 40 Hz, 50% duty cycle) administered simultaneously. Cognitive outcomes were assessed using the Mini-Mental State Examination (MMSE) and ADAS-Cog at baseline, post-treatment, and at the 12-week follow-up.

RESULTS: Significant improvements were observed in the active group across both scales. MMSE scores increased from 21.89 ± 2.35 to 27.22 ± 1.96 (p = 0.0001), with sustained effects at follow-up. ADAS-Cog scores decreased from 34.78 ± 4.99 to 18.22 ± 4.4 (p < 0.0001). Post hoc analyses revealed significant changes in attention, recall, praxis, and executive domains. No serious adverse events were reported.

CONCLUSION: Combined tDCS and iNIRS therapy significantly enhances cognitive performance in patients with MCI and mild AD. This synergistic, non-invasive approach may offer a promising therapeutic strategy to delay cognitive decline and reduce care-related burdens.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07290686; Registration date 14 December 2023.},
}

@article {pmid41997210,
year = {2026},
author = {Chakravarty, S and Revi, N and Bijukumar, D},
title = {Development and initial characterization of Ang-2 decorated exosome-liposome hybrid nanocarriers for BBB targeting capability: An evaluation of LRP-1 receptor mediated endocytosis.},
journal = {Biomedical materials (Bristol, England)},
volume = {},
number = {},
pages = {},
doi = {10.1088/1748-605X/ae6164},
pmid = {41997210},
issn = {1748-605X},
abstract = {Central Nervous System (CNS) diseases, including Parkinson's, Alzheimer's, and brain tumors, are among the most challenging conditions to treat and are associated with high mortality rates. A significant obstacle in conventional treatment methods for CNS diseases is that many drugs struggle to penetrate the blood-brain barrier (BBB), which diminishes their effectiveness. The primary aim of the current study was to develop and characterize a hybrid nanocarrier composed of exosomes and liposomes to facilitate targeted drug delivery across the BBB for future CNS disease therapies. To achieve targeted uptake, we conjugated the exosome-liposome hybrid to the Angiopep-2 peptide (ANG-2), which has a specific affinity for the LRP-1 receptor, found on endothelial cells of the blood-brain barrier. Our results indicate that exosome-liposome hybrid nanoparticles exhibit significantly greater stability than exosomes alone. Moreover, the LRP-1 ligand-decorated exo-lipo hybrids effectively targeted U87 cells (a model cell line that expresses LRP-1) more efficiently than HEK293 (a cell line with low LRP-1 expression). Additionally, our findings demonstrated that these nanocarriers successfully evaded lysosomal degradation in U87 cells. We also assessed the barrier-crossing efficiency of the nanocarriers in vivo using zebrafish embryos.},
}

@article {pmid41997281,
year = {2026},
author = {Yang, YP and Nicol, CJB and Yen, C and Chiang, MC},
title = {Glutathione-conjugated gold nanoparticles mitigate amyloid-beta-induced neuroinflammation and tauopathy through inhibition of NF-κB, the NLRP3 inflammasome axis in 3D human neural stem cell models.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {115030},
doi = {10.1016/j.yexcr.2026.115030},
pmid = {41997281},
issn = {1090-2422},
abstract = {Neuroinflammation and tauopathy are central pathological features of Alzheimer's disease (AD), often exacerbated by amyloid-β (Aβ) accumulation. This study evaluated the therapeutic potential of glutathione-conjugated gold nanoparticles (GSH-AuNPs) in mitigating Aβ-induced cytotoxicity and inflammation using a physiologically relevant 3D human neural stem cell (hNSCs) model cultured within a gelatin scaffold. This 3D system provided a tissue-like microenvironment to closely mimic in vivo conditions. GSH-AuNP treatment significantly rescued Aβ-induced loss of cell viability and suppressed tumor necrosis factor-α (TNF-α) secretion. At the molecular level, GSH-AuNPs downregulated the expression of key inflammatory mediators, including IKKα, IKKβ, and NF-κB (p65), and inhibited nuclear translocation of p65. Additionally, GSH-AuNPs attenuated the expression of proinflammatory enzymes iNOS and COX-2 and suppressed activation of the NLRP3 inflammasome, as evidenced by reduced levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18. Proteostasis was improved by restoring chymotrypsin-like proteasome activity and reducing phosphorylated tau accumulation. Furthermore, GSH-AuNPs enhanced cellular resilience by upregulating heat shock factor 1 (HSF1) and normalizing the expression of key molecular chaperones HSP27, HSP70, and HSP90. Our findings highlight the multifaceted protective effects of GSH-AuNPs in counteracting Aβ-induced neuroinflammation and tauopathy. These results support the potential application of GSH-AuNPs as a nanomedicine-based therapeutic strategy for AD.},
}

@article {pmid41997401,
year = {2026},
author = {Sun, X and Deng, W and Yu, J and Xu, X},
title = {From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178867},
doi = {10.1016/j.ejphar.2026.178867},
pmid = {41997401},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.},
}

@article {pmid41997458,
year = {2026},
author = {Chen, F and Lv, X and Xiang, K and Lin, X and Dai, C and Wei, C and Zhang, Y and Liu, J and Li, J},
title = {Pterostilbene targets microglia-mediated neuroinflammation for Alzheimer therapy.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110382},
doi = {10.1016/j.jnutbio.2026.110382},
pmid = {41997458},
issn = {1873-4847},
abstract = {Microglia-mediated neuroinflammation is a key driver of Alzheimer's disease (AD) progression, exacerbating neuronal damage and pathological changes. Pterostilbene (PTE), a natural anti-inflammatory stilbenoid, shows neuroprotective potential in AD, but its specific mechanism in regulating AD-related neuroinflammation remains unclear. Here, we explored the anti-neuroinflammatory effect and mechanisms of PTE against AD. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated intragastrically with PTE for 4 weeks, followed by evaluation of cognitive function and pathological changes. Amyloid-β (Aβ) burden, Tau protein phosphorylation, microglial activation and proinflammatory cytokines production were analyzed. To further investigate the potential mechanism of PTE, an integrated approach combining network pharmacology, RNA sequencing, molecular docking, molecular dynamics simulations, and cell transfection techniques were conducted. Our results showed that PTE treatment improved cognitive impairment, Aβ deposits, Tau protein phosphorylation, microglia activation, and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in vivo and in vitro. Notably, molecular docking predicted that PTE has binding affinity for JAK2 at LYS-857, LYS-882, and LEU-932. Consistently, site-directed mutagenesis reduced the inhibitory effect of PTE on JAK2/STAT3 phosphorylation, supporting JAK2 as a functional target. Meanwhile, we revealed that PTE effectively inhibited activation of microglia in the APP/PS1 mice by regulating JAK2-STAT3 pathway. These findings indicate that PTE treatment could attenuate microglia-mediated neuroinflammation via regulating JAK2-STAT3 signaling pathway, which might provide a novel option to elucidate the effects of PTE on AD.},
}

@article {pmid41997498,
year = {2026},
author = {Pillarisetti, S and Alfieri, R and Palumbo, P and Sarmento, B and Celia, C and Fresta, M},
title = {Oxidative cues as theranostic switches for the ROS-responsive Nanotheranostics in oxidative stress-driven diseases.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114933},
doi = {10.1016/j.jconrel.2026.114933},
pmid = {41997498},
issn = {1873-4995},
abstract = {Nanotheranostics (NTs) are nanoscale systems that combine disease diagnosis and targeted therapy. They often respond to specific signals, such as reactive oxygen species (ROS). These platforms leverage elevated ROS levels associated with diseases, such as neurodegeneration, cancer, cardiovascular disorders, and inflammation, to control drug release and support targeted imaging. In this review, we have described the different roles of ROS in neurological disorders (Alzheimer's disease), cancer, cardiovascular diseases (including atherosclerosis and myocardial infarction), and joint inflammation (arthritis). We also discuss the relative applications of ROS-responsive NTs. By integrating diagnosis and treatment, ROS-responsive NTs can improve treatment outcomes, reduce side effects, and help clinicians track disease progression and therapeutic response in real time. Advanced NTs are sensitive to additional triggers, such as pH, thermal, and hypoxic conditions. This sensitivity improves accuracy and outcomes for ROS-driven diseases. This strategy shows promise for precision medicine by using multifunctional, stimulus-activated nanomedicines to treat diseases driven by oxidative stress. This review summarizes recent advances, focusing on nanomaterial composition and chemistry for ROS response or scavenging to improve diagnosis and treatment. Finally, we explore current advances and perspectives on ROS-based NTs across ROS-driven diseases.},
}

@article {pmid41985900,
year = {2026},
author = {Nonino, F and Minozzi, S and Sambati, L and Del Giovane, C and Baldin, E and Bassi, MC and De Santis, C and Gonzalez-Lorenzo, M and Vignatelli, L and Filippini, G and Richard, E},
title = {Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease.},
journal = {The Cochrane database of systematic reviews},
volume = {4},
number = {4},
pages = {CD016297},
pmid = {41985900},
issn = {1469-493X},
mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Cognitive Dysfunction/drug therapy/etiology ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Aged ; },
abstract = {RATIONALE: Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline.

OBJECTIVES: To assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease.

SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025.

ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. We included both parallel-group and cluster designs.

OUTCOMES: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid-related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any-cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment.

RISK OF BIAS: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance.

SYNTHESIS METHODS: We meta-analysed results for each outcome within each comparison using the inverse variance method and the random-effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high.

INCLUDED STUDIES: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months. The 17 studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months. All studies were funded by the pharmaceutical industry.

SYNTHESIS OF RESULTS: Below, we report the results of the studies at 18 months. Cognitive function Compared to placebo, amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) scale (standardised mean difference (SMD) -0.11, 95% confidence interval (CI) -0.16 to -0.06; 13 studies, 9895 participants; moderate certainty). Dementia severity Amyloid-beta-targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR-SB (Clincal Dementia Rating Sum of Boxes) scale (SMD -0.12, 95% CI -0.24 to -0.00; 9 studies, 8053 participants; low certainty). Functional ability Amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS-ADL-MCI (Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty). Adverse events Amyloid-beta-targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty). Three studies assessing any ARIA H showed heterogeneous results (I[2] = 81%), which prevented pooled analysis. At 18 months, amyloid-beta-targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty). We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects).

AUTHORS' CONCLUSIONS: The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action.

FUNDING: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia-Romagna, Bologna, Italy. The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health.

REGISTRATION: Protocol (2025): PROSPERO registration number CRD420251114325.},
}

Humans
*Alzheimer Disease/complications/drug therapy
*Cognitive Dysfunction/drug therapy/etiology
*Amyloid beta-Peptides/antagonists & inhibitors/immunology
Randomized Controlled Trials as Topic
*Antibodies, Monoclonal/therapeutic use/adverse effects
Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
Aged

@article {pmid41986146,
year = {2026},
author = {Ebani, EJ and Yadav, D and Knight-Greenfield, A and Gardella, J and Moirano, J and Intorcia, B and RoyChoudhury, A and Keil, SA and Nordvig, AS and Blum, S and Lin, M and Osborne, JR and Chiang, GC and Ivanidze, J},
title = {Cross-Platform Concordance of Quantitative Amyloid PET Z-Scores in a Real-World Clinical Cohort of Patients with Cognitive Impairment and Suspected Alzheimer Disease.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9354},
pmid = {41986146},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Normative modeling tools are FDA-approved clinical software applications that enable quantitative amyloid PET analysis in routine clinical practice, however implementation differences may yield non-interchangeable Z-scores, with implications for diagnosis and treatment eligibility for patients with cognitive impairment and/or suspected Alzheimer disease. This study evaluated the agreement of Z-scores derived from two widely used clinical software packages in a real-world cohort of patients with cognitive impairment/Alzheimer disease.

MATERIALS AND METHODS: Amyloid PET from 100 consecutive patients with cognitive impairment/Alzheimer disease obtained as part of standard-of-care evaluation at a single institution were retrospectively reviewed. Amyloid PET were post-processed using syngo.via MI Neurology (Siemens Healthineers) and MIMneuro (MIM Software/GE Healthcare). Regional Z-scores were obtained for the temporal, precuneus, posterior cingulate, parietal, frontal, and anterior cingulate cortices. Z-scores were compared per patient and stratified by Centiloid burden (low/intermediate/high: < 20/20-30/>30). Agreement was evaluated using Bland-Altman analysis and Deming regression.

RESULTS: Agreement between Syngo.via and MIMneuro varied by region. When regional Z-scores were averaged into a per-patient composite measure, overall bias was near-zero, with tight limits of agreement (slope = 0.97 [95% CI 0.93-1.02], intercept = 0.11 [95% CI -0.05-0.26]), indicating minimal proportional and constant bias between platforms. Bland-Altman analysis showed small bias and narrow limits of agreement (LoA) in the low-centiloid group (mean bias -0.19, 95% LoA -0.93 to +0.55) and the greatest divergence in the intermediate group (mean bias -0.44, LoA -2.02 to +1.14). In the high-centiloid group, bias remained small (+0.16) with wider LoA (-1.92 to +2.24). Temporal cortex Deming regression demonstrated proportional and constant bias (slope = 0.70 [95% CI 0.66-0.74], intercept = 0.34 [95% CI 0.07-0.61]), indicating systematic underestimation of high Z-scores by MIM relative to Syngo.via.

CONCLUSIONS: There was overall concordance between Syngo.Via and MIMneuro quantitative amyloid PET analysis software packages, however with significant region- and amyloid burden-dependent variability that increased in the intermediate-centiloid group. These differences may influence interpretation and determination of treatment eligibility in borderline cases, emphasizing that Z-scores from different commercial platforms should not be used interchangeably without cross-validation.},
}

@article {pmid41986822,
year = {2026},
author = {Hazar-Yavuz, AN and Ertas, B and Kaya, RK and Topal, F and Kabataş, GS and Altuntaş, C and Kabasakal, L and Yazir, Y and Cam, ME},
title = {Modulation of Amyloid and Tau Pathology by Empagliflozin in a High-Fat Diet and Streptozotocin-Induced Type 2 Diabetes-Associated Alzheimer's Model.},
journal = {The European journal of neuroscience},
volume = {63},
number = {8},
pages = {e70495},
doi = {10.1111/ejn.70495},
pmid = {41986822},
issn = {1460-9568},
support = {SAG-A-110618-0292//Marmara Üniversitesi/ ; },
mesh = {Animals ; *Benzhydryl Compounds/pharmacology/therapeutic use ; *Glucosides/pharmacology/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology/etiology ; Diet, High-Fat/adverse effects ; *tau Proteins/metabolism ; *Diabetes Mellitus, Type 2/complications/metabolism/drug therapy ; Male ; Rats ; *Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Experimental/metabolism/complications/drug therapy ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; *Neuroprotective Agents/pharmacology ; Streptozocin ; Rivastigmine/pharmacology ; Disease Models, Animal ; Brain/metabolism/drug effects/pathology ; Rats, Wistar ; Blood Glucose/drug effects/metabolism ; },
abstract = {Type 2 diabetes mellitus (T2DM) contributes notably to the development and progression of Alzheimer's disease (AD) through overlapping pathological mechanisms such as insulin resistance, amyloid-β (Aβ) accumulation and tau hyperphosphorylation. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have recently emerged as promising candidates for neuroprotection in metabolic disorders. The present work explored the potential therapeutic impact of the SGLT2 inhibitor empagliflozin (EMPA) compared with the acetylcholinesterase inhibitor rivastigmine (RIV) in a T2DM-induced AD rat model. The T2DM-AD model was established using a high-fat diet in combination with subsequent low-dose streptozotocin (35 mg/kg) administration. Metabolic, behavioural, biochemical, molecular and histopathological parameters were assessed to evaluate disease progression and treatment efficacy. EMPA significantly improved glucose metabolism, lowered nonfasting blood glucose, enhanced oral glucose tolerance and restored insulin levels in peripheral and central tissues. EMPA ameliorated short-term and spatial memory deficits and reduced Aβ and phosphorylated tau levels in the brain, serum and pancreas and normalized acetylcholinesterase and glycogen kinase-3β expression. Histological and immunohistochemical analyses corroborated these neuroprotective effects, revealing reduced neurodegeneration and proteinopathy in the cerebral cortex and hippocampus. EMPA exerts multifaceted neuroprotective and metabolic benefits in a T2DM-induced AD model, offering a therapeutic advantage over RIV by targeting both peripheral metabolic dysfunction and central neurodegeneration. By demonstrating that modulation of systemic glucose homeostasis can directly influence amyloid and tau pathology as well as cognitive outcomes, these findings provide important insight into the metabolic-neurodegenerative interface and highlight SGLT2 inhibition as a promising strategy for diabetes-associated cognitive decline and AD within the field of neuroscience.},
}

Animals
*Benzhydryl Compounds/pharmacology/therapeutic use
*Glucosides/pharmacology/therapeutic use
*Alzheimer Disease/metabolism/drug therapy/pathology/etiology
Diet, High-Fat/adverse effects
*tau Proteins/metabolism
*Diabetes Mellitus, Type 2/complications/metabolism/drug therapy
Male
Rats
*Amyloid beta-Peptides/metabolism
*Diabetes Mellitus, Experimental/metabolism/complications/drug therapy
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
*Neuroprotective Agents/pharmacology
Streptozocin
Rivastigmine/pharmacology
Disease Models, Animal
Brain/metabolism/drug effects/pathology
Rats, Wistar
Blood Glucose/drug effects/metabolism

@article {pmid41987015,
year = {2026},
author = {Morales, MJ and Ricketts, S and Grudzen, CR and Brody, AA and Chodosh, J and Goldfeld, K and Shah, MN and , },
title = {Bridging the Gap Between the ED and Home: The Community Paramedic-Led Transitions Intervention for Persons Living With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70403},
pmid = {41987015},
issn = {1532-5415},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U19 AG078105-01A1/AG/NIA NIH HHS/United States ; },
abstract = {More than 6 million persons living with dementia (PLWD) in the United States rely on the emergency department (ED) for unscheduled care, with up to half discharged home after treatment. The ED-to-home transition poses significant challenges for PLWD and their care partners (referred to as "dyads"), contributing to high rates of ED revisits and adverse outcomes. The Community Paramedic-led Transitions Intervention (CPTI) was developed to address these challenges by adapting the validated Care Transitions Intervention for the ED setting. Delivered by trained community paramedics, CPTI is a short-term 30-day program that includes one home visit and up to three follow-up phone calls. Using a coaching model, paramedic coaches work with members of the dyad to strengthen their knowledge, skills, and confidence to manage their health and successfully navigate the health care system. CPTI is being implemented as part of Emergency Departments LEading the Transformation of Alzheimer's and Dementia Care (ED-LEAD), a cluster-randomized pragmatic trial testing 3 interventions designed to improve outcomes for PLWD discharged home from the ED across 14 health systems and 79 EDs nationwide. This paper describes the CPTI model as implemented within ED-LEAD, detailing its theoretical foundation, structure, training curriculum, workflow integration, and implementation monitoring. This framework can provide a model for health systems, provider groups, and emergency medical service agencies interested in adopting this innovative approach and implementing the CPTI. Insights from its implementation within ED-LEAD will guide future efforts to improve post-ED outcomes and continuity of care for PLWD and their care partners.},
}

@article {pmid41987849,
year = {2026},
author = {Xu, Y and Chen, D and Ye, Q and Zhang, P and Shi, J and Li, S and Sun, Y and Zhao, Z and Tang, Y and Zhang, P and Tang, Z},
title = {Emerging Neural Recording and Neurostimulation Technologies Based on Brain-Computer Interface: A Promising Approach for Neuropsychiatric Disorders.},
journal = {MedComm},
volume = {7},
number = {},
pages = {e70739},
pmid = {41987849},
issn = {2688-2663},
abstract = {Neurological and psychiatric disorders, arising from disruptions in neural circuitry, pose a major and growing challenge to global healthcare systems. Brain-computer interface (BCI) technology has emerged as a promising approach, enabling direct communication between the brain and external devices. By facilitating bidirectional interaction with the nervous system, BCIs open new avenues for both diagnosis and treatment. In this review, we examine recent advances in recording and stimulation technologies within the BCI framework and evaluate their therapeutic potential across major neuropsychiatric disorders. We focus particularly on post-stroke motor rehabilitation as a representative paradigm, providing detailed analysis of the mechanisms, clinical evidence, and future prospects of endovascular BCI, BCI-integrated epidural spinal cord stimulation, and BCI-driven deep brain stimulation. We further extend the discussion to movement disorders such as Parkinson's disease and epilepsy, as well as cognitive and psychiatric conditions including Alzheimer's disease and depression, highlighting how BCI-based approaches enable symptom detection and closed-loop neuromodulation. Additionally, we address ethical and societal considerations accompanying clinical translation of these advanced neurotechnologies. By integrating current evidence, this review highlights a paradigm shift toward more active, precise, and personalized neural rehabilitation enabled by BCI systems, while outlining key challenges and future directions for research and clinical application.},
}

@article {pmid41987879,
year = {2026},
author = {Manganotti, P and Palacino, F and Pavan, S and Benussi, A},
title = {Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1806471},
pmid = {41987879},
issn = {1663-4365},
abstract = {Epilepsy and epileptiform activity represent underrecognized yet clinically significant features of neurodegenerative dementias, with emerging evidence suggesting they may contribute to disease progression rather than merely representing epiphenomena of neuronal loss. This comprehensive review examines the epidemiology, clinical presentation, electroencephalographic findings, and pathophysiological mechanisms underlying seizure activity in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Meta-analytic data demonstrate elevated seizure prevalence across all three conditions, with cumulative probabilities of 13.4% for AD, 14.7% for DLB, and 3.0% for FTD, representing risk elevations of approximately 6- to 10-fold compared to age-matched controls. Critically, subclinical epileptiform activity detected through prolonged electroencephalographic monitoring affects up to 42-54% of AD patients and is associated with 1.5-fold accelerated cognitive decline. Each dementia subtype exhibits characteristic electroencephalographic signatures: AD demonstrates progressive spectral slowing with predominantly left temporal epileptiform discharges; DLB shows highly characteristic slowing of the dominant rhythm below 8 Hz with high diagnostic accuracy; and FTD displays relatively preserved background activity with frontal-temporal hypoconnectivity. We synthesize evidence from transcranial magnetic stimulation studies demonstrating distinct patterns of cortical excitability alterations across these conditions, with AD showing bilateral increases in cortical excitability and reduced GABAergic and cholinergic inhibition. Building upon these observations, dementia-associated epilepsy may be conceptualized within the framework of system epilepsies, arising from dysfunction of vulnerable neural networks rather than discrete lesions. This paradigm shift has profound therapeutic implications, supporting network-targeted interventions and the potential disease-modifying role of antiseizure medications. We conclude by presenting clinical recommendations for monitoring and treatment, emphasizing the need for prolonged electroencephalographic evaluation and consideration of empirical treatment for subclinical epileptiform activity associated with cognitive fluctuations.},
}

@article {pmid41989792,
year = {2026},
author = {Upadhyay, R and Jain, A and Trivedi, K and Desavathu, M},
title = {Nanomedicines for Neurodegenerative Ageing: Nasal Delivery Innovations for Alzheimer's and Parkinson's Disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-40},
doi = {10.1080/1061186X.2026.2659210},
pmid = {41989792},
issn = {1029-2330},
abstract = {Alzheimer's disease and Parkinson's disease are progressive, age-related neurodegenerative disorders with increasing global prevalence, yet their treatment remains challenging despite the availability of multiple therapeutic agents. Conventional formulations are often limited by poor solubility, restricted blood-brain barrier penetration, extensive first-pass metabolism, short elimination half-life, low brain bioavailability, and systemic adverse effects. In recent years, the nose-to-brain route has emerged as a promising strategy for delivering therapeutics directly to the brain. This approach offers non-invasive administration, rapid onset of action, direct brain targeting via olfactory and trigeminal pathways, reduced systemic exposure, bypassing of first-pass metabolism, improved bioavailability, and enhanced patient compliance. To exploit these advantages, a variety of biodegradable nanocarrier systems have been investigated, including lipid-based and polymer-based nanoparticles, nasal gel-based systems, nanoemulsions, nanosuspensions, hybrid nanoparticles, and nasal sprays. This review provides a comprehensive synthesis of preclinical studies evaluating nose-to-brain nanocarrier-based delivery strategies for Alzheimer's and Parkinson's disease, with particular emphasis on their pharmacokinetic and pharmacodynamic performance. Collectively, the evidence indicates that nose-to-brain nanocarriers can effectively address key limitations of conventional therapies by enhancing brain targeting and therapeutic efficacy. However, successful clinical translation will require addressing formulation-related challenges such as mucociliary clearance, nasal irritation, burst drug release, and long-term safety, alongside well-designed clinical studies. Future research should therefore focus on exploring emerging delivery platforms to further advance nose-to-brain strategies for the management of neurodegenerative diseases.},
}

@article {pmid41989985,
year = {2026},
author = {Sun, M and Lu, Z and Chen, WM and Lv, S and Fu, N and Yang, Y and Wang, Y and Miao, M and Wu, SY and Zhang, J},
title = {N-Acetylcysteine and Dementia Risk in Elderly Patients.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {4},
pages = {e70212},
doi = {10.1002/gps.70212},
pmid = {41989985},
issn = {1099-1166},
mesh = {Humans ; *Acetylcysteine/administration & dosage/therapeutic use ; Male ; Aged ; Female ; Taiwan/epidemiology ; *Dementia/epidemiology/prevention & control ; Aged, 80 and over ; *Pulmonary Disease, Chronic Obstructive/drug therapy/epidemiology ; Proportional Hazards Models ; Risk Factors ; Dose-Response Relationship, Drug ; Propensity Score ; },
abstract = {OBJECTIVE: This study aimed to investigate the association between N-acetylcysteine (NAC) use and dementia risk in elderly individuals diagnosed with Chronic Obstructive Pulmonary Disease (COPD).

METHODS: Utilizing Taiwan's National Health Insurance Research Database (NHIRD), we conducted a population-based cohort study of 105,144 elderly COPD patients to investigate the association between NAC use and dementia risk. Propensity score matching (PSM) ensured balanced covariates between NAC users and nonusers. Cox regression analysis and Poisson Regression analysis were employed to assess dementia risk, considering NAC dosage, treatment duration, and comorbidities. Competing risk analysis and Kaplan-Meier method were used to account for mortality risk and estimate dementia incidence, respectively.

RESULTS: Elderly NAC users demonstrated a significant association with a lower dementia risk (adjusted hazard ratio [aHR]: 0.76, 95% confidence interval [CI]: 0.74-0.78). Higher daily NAC intake was associated with a dose-dependent decline in dementia risk, with optimal benefits observed at an average daily dose of 1.61 defined daily doses (DDD). Stratification by cumulative defined daily doses (cDDD) of NAC revealed a consistent dose-response relationship, with progressively diminished dementia risk across quartiles of cDDD. Notably, NAC use was associated with a lower risk of Alzheimer's dementia (aHR: 0.68, 95% CI: 0.66-0.70) compared to non-NAC antimucolytic users.

CONCLUSIONS: NAC use is associated with a dose-dependent reduction in dementia risk among elderly COPD patients, particularly for Alzheimer's dementia. Our findings underscore the potential of NAC as a potential protective factor against dementia in this vulnerable population, warranting further investigation and consideration in clinical practice.},
}

Humans
*Acetylcysteine/administration & dosage/therapeutic use
Male
Aged
Female
Taiwan/epidemiology
*Dementia/epidemiology/prevention & control
Aged, 80 and over
*Pulmonary Disease, Chronic Obstructive/drug therapy/epidemiology
Proportional Hazards Models
Risk Factors
Dose-Response Relationship, Drug
Propensity Score

@article {pmid41990984,
year = {2026},
author = {Xu, G and Gao, J and Wang, T and Wu, H and Liu, S and Ji, Y and Wang, P and Guo, M},
title = {Differential modulation of EEG microstate spatiotemporal dynamics by rTMS and iTBS correlates with clinical improvement in Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150323},
doi = {10.1016/j.brainres.2026.150323},
pmid = {41990984},
issn = {1872-6240},
abstract = {BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with Alzheimer's Disease (AD), potentially modulating aberrant functional connectivity. Electroencephalography (EEG) microstates represent transient large-scale resting networks and have emerged as candidate markers for AD. However, their modulation by repetitive TMS (rTMS) and intermittent theta burst stimulation (iTBS) protocols remains to be elucidated.

METHODS: Resting-state EEG was recorded from 28 AD patients at baseline and following the 1st, 7th, and 14th sessions of rTMS or iTBS treatment. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates, which were then subjected to source localization to identify their corresponding cortical regions. Longitudinal changes within subjects in clinical status and microstate parameters (duration, occurrence, coverage, transition probability) were evaluated with one-way repeated-measures analysis of variance, and differences between rTMS and iTBS groups were assessed using t-tests.

RESULTS: Four microstates (MS A-D) were identified from EEG data. rTMS predominantly induced sustained suppression of MS-B, whereas iTBS elicited early-phase increases in MS-C activity. Clinical symptoms improvement following TMS correlated with increased MS-C and decreased MS-B activity. Source localization revealed rTMS predominantly modulated MS-B generators in the occipital cortex (impacting visual and dorsal attention networks), while iTBS preferentially engaged MS-C generators in the parietal cortex (affecting sensorimotor and frontoparietal networks).

CONCLUSIONS: We identified distinct EEG microstates and their underlying cortical generators associated with clinical improvement in AD following treatment with rTMS and iTBS protocols. The results demonstrate protocol-specific spatiotemporal modulation profiles and temporal dynamics, highlighting differential neural mechanisms of rTMS and iTBS.},
}

@article {pmid41991301,
year = {2026},
author = {Guo, SF and Wang, EL and Zeng, JX and Hou, YQ},
title = {[Research progress on the pathogenesis of Alzheimer's disease related to infectious pathogens].},
journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]},
volume = {60},
number = {4},
pages = {631-639},
doi = {10.3760/cma.j.cn112150-20250607-00522},
pmid = {41991301},
issn = {0253-9624},
support = {2024ZDXK0065//Key Discipline Project of Shanghai Municipal Health Commission/ ; 24SJYXZDA06//Key Discipline Project of Shanghai Songjiang District Municipal Health Commission/ ; 23ZR1457300//Project supported by the Shanghai Committee of Science and Technology/ ; 82401655//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology ; Blood-Brain Barrier ; },
abstract = {Alzheimer's disease (AD), one of the most prevalent neurodegenerative disorders, is clinically characterized by progressive memory decline and cognitive impairment, predominantly affecting the elderly population. The pathogenesis of AD remains incompletely elucidated, and effective curative treatments are currently lacking. Notably, China has become the country with the highest number of AD cases globally. Growing evidence suggests that infections may play a crucial role in the initiation and progression of AD, though the precise mechanisms remain unclear. This review systematically examines how infectious agents participate in AD pathogenesis through key pathways including: driving neuroinflammatory responses, disrupting the blood-brain barrier and mediating central nervous system invasion, programmed cell death, and modulating epigenetic regulation and gene expression. We focus on recent advances in understanding the associations between AD and diverse pathogens including viruses, bacteria, fungi, and parasites. Finally, we discuss current anti-infective therapeutic strategies and outline future research priorities, aiming to provide novel theoretical foundations and investigative approaches for AD prevention and treatment.},
}

Humans
*Alzheimer Disease/microbiology/etiology
Blood-Brain Barrier

@article {pmid41975524,
year = {2026},
author = {More, SA and Mundke, RN and Agrawal, YO and Awathale, SN and Goyal, SN and Nakhate, KT and Rathod, SS},
title = {Intracerebroventricular streptozotocin-induced animal model of Alzheimer's disease: revealing dose optimization, administration regimen, and molecular pathways.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41975524},
issn = {1738-6055},
abstract = {UNLABELLED: Streptozotocin (STZ) is a commonly administered chemical via the intracerebroventricular (ICV) route in rodents to induce Alzheimer’s disease (AD)-like symptoms. Unfortunately, available research articles from different laboratories suggest inconsistency in doses, administration schedules, and target brain regions. For instance, ICV dose varies from 1.5 to 5 mg/kg either unilaterally or bilaterally, for 7 days to 21 days, as a single or multiple injections. Therefore, it is challenging for novice investigators to select the optimal doses, treatment durations, and targeted molecular pathways while employing STZ to induce AD-like conditions in experimental animals. In this background, the information related to the STZ-induced animal model of AD should be available on a single platform to aid researchers in selecting the suitable doses and regimens that suit their research objectives. The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as streptozotocin, intracerebroventricular, dosage optimization, Alzheimer’s disease, neuroinflammation, and oxidative stress. The present review highlights the articles published up to May 2025, with predefined inclusion (ICV-STZ model, cognitive/biochemical outcomes) and exclusion criteria (non-peer-reviewed papers, studies lacking behavioral or molecular endpoints, and studies older than 20 years). We have attempted to present the optimal dose, administration regimen, and biological process for inducing ICV-STZ AD models based on their advantages and limitations. According to the comparative quantitative evaluation of preclinical investigations, bilateral ICV administration of STZ at a cumulative dose of 3 mg/kg (1.5 mg/kg on days 1 and 3) displays the most reliable and physiologically relevant regimen. Studies also demonstrated that between 14 and 21 days after injection, this regimen reliably causes oxidative stress, neuroinflammation, cholinergic dysfunction, and progressive cognitive impairments, offering a balanced picture of physiological, histological, and behavioral alterations. However, unlike transgenic models, the ICV-STZ paradigm generally fails to develop extensive amyloid-beta plaque deposition or well-formed neurofibrillary tangles. Hence, more quantitative investigations are necessary to validate this optimization.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid41981211,
year = {2026},
author = {Zhu, TT and Liu, PM and Hashimoto, K and Yang, JJ},
title = {Clinical innovations and future directions of nanoparticles in the treatment of psychiatric and neurological disorders.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41981211},
issn = {1476-5578},
support = {82171189//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81971020//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy. Lipid, polymeric, inorganic, and hybrid NPs can be engineered to traverse the blood-brain barrier (BBB) via receptor/transporter pathways, target specific cell types, and deliver sustained or stimuli-responsive release. Beyond drug delivery, NPs improve imaging, enable gene/RNA therapeutics, and support anti-inflammatory and neuroprotective strategies, advancing precision medicine. Preclinical studies in depression, schizophrenia, Alzheimer's disease, and Parkinson's disease show superior exposure, target engagement, and behavioral or cognitive benefits versus free drugs, including photothermal/photodynamic and nanobody-based approaches. Clinically, translation remains early: a handful of CNS-directed candidates (e.g., gold-based bioenergetic agents, intranasal lipid formulations, liposomal modulators) are in trials, while approvals largely lie outside CNS indications. Key hurdles include variable BBB integrity, immunogenicity and protein-corona effects, manufacturing and stability constraints, and limited effect-site exposure-response data in humans. This review outlines a translational playbook: model-informed development linking formulation to brain interstitial exposure; Quality-by-Design chemistry, manufacturing, and controls (CMC); stratified, adaptive trials with population PK/PD and harmonized biomarkers; and proactive safety monitoring with long-term registries. We also highlight NP strategies targeting the gut-brain axis-delivering probiotics, metabolites, or antimicrobials-as complementary routes to modulate neuroinflammation and circuit function. With rigorous clinical science, manufacturing quality, and safety governance embedded from the outset, nanotechnology is positioned to deliver safer, more effective, and potentially disease-modifying therapies for CNS disorders.},
}

@article {pmid41981256,
year = {2026},
author = {Shao, B and Zeng, Y and Ju, J},
title = {Dynamic collaboration between mitochondria and organelles: mechanisms, functions, and disease implications.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {4},
pages = {},
pmid = {41981256},
issn = {1573-675X},
support = {32572715//The National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mitochondria/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neoplasms/metabolism/pathology/genetics ; Animals ; *Organelles/metabolism ; Alzheimer Disease/metabolism ; Endoplasmic Reticulum/metabolism ; Oxidative Stress ; },
abstract = {In recent years, numerous studies have revealed that dysregulation of mitochondria-organelle interactions is a common feature underlying various pathological processes and pathogen infections. For instance, in Alzheimer's disease (AD), dysfunction of mitochondrial-associated ER membranes (MAMs) leads to calcium overload and oxidative stress, while cancer cells enhance glycolysis by remodeling mitochondria-Golgi interactions. Targeting these key interacting nodes has shown significant therapeutic potential. Although technological advances have uncovered some underlying mechanisms, the spatiotemporal dynamics, tissue specificity, and causal role of organelle interactions in diseases remain unclear. In-depth understanding of these collaborative networks will provide new targets for the treatment of cancer, metabolic syndrome, and neurodegenerative diseases, and also create novel possibilities for elucidating pathogen-host interaction mechanisms and developing anti-infective therapies. Given the importance of dynamic mitochondria-organelle collaboration in disease treatment, this review first focuses on analyzing the molecular mechanisms underlying this crosstalk. Building on this, the dysregulation of mitochondria-organelle collaboration in diseases is discussed in depth, with a particular focus on cancer, cardiovascular diseases, metabolic syndrome, and neurodegenerative diseases. Finally, the potential therapeutic strategies targeting organelle interactions are summarized and analyzed. In conclusion, the information in this manuscript offers a new way to think about and treat several serious illnesses.},
}

Humans
*Mitochondria/metabolism
Neurodegenerative Diseases/metabolism/pathology
Neoplasms/metabolism/pathology/genetics
Animals
*Organelles/metabolism
Alzheimer Disease/metabolism
Endoplasmic Reticulum/metabolism
Oxidative Stress

@article {pmid41981347,
year = {2026},
author = {Sengupta, P and Mukhopadhyay, D},
title = {Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41981347},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Amyloid beta-Peptides/toxicity ; *Cell Nucleus/metabolism/drug effects ; *Receptor, IGF Type 1/metabolism ; *Cyclin D1/metabolism ; Cell Line, Tumor ; *Cell Cycle/drug effects ; Active Transport, Cell Nucleus/drug effects ; Phosphorylation/drug effects ; Neurons/metabolism/drug effects ; Models, Biological ; Protein Transport/drug effects ; },
abstract = {Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G2 phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Amyloid beta-Peptides/toxicity
*Cell Nucleus/metabolism/drug effects
*Receptor, IGF Type 1/metabolism
*Cyclin D1/metabolism
Cell Line, Tumor
*Cell Cycle/drug effects
Active Transport, Cell Nucleus/drug effects
Phosphorylation/drug effects
Neurons/metabolism/drug effects
Models, Biological
Protein Transport/drug effects

@article {pmid41982209,
year = {2026},
author = {Ubuka, T and Yuyama, K and Genjima, A and Nagakura, M and Kato, K and Hayashi, S and Makino, N and Yamane, T and Hirose, T and Yamane, Y},
title = {Mitigating cognitive decline in Alzheimer's disease dementia by enhancing cognitive reserve through neuroplasticity in addition to amyloid-β reduction.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1769431},
pmid = {41982209},
issn = {1663-4365},
}

@article {pmid41984492,
year = {2026},
author = {Chiu, PY and Chiu, HJ and Wei, CY and Tzeng, RC and Chang, HT and Chen, HM},
title = {Dementia with Lewy bodies clinical syndrome (DLBCS) questionnaire: A simple tool for the clinical screening of DLB.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441187},
doi = {10.1177/13872877261441187},
pmid = {41984492},
issn = {1875-8908},
abstract = {BackgroundDementia with Lewy bodies (DLB) remains underdiagnosed due to overlapping clinical features with Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Early recognition is crucial, as DLB has distinct prognostic and therapeutic implications.ObjectiveThis study aimed to develop and validate a brief, clinically applicable screening instrument to improve bedside recognition of DLB and to compare its performance with established diagnostic approaches.MethodsWe designed the Dementia with Lewy Bodies Clinical Screening Questionnaire (DLBCSQ) and an extended version (DLBCSQ11) incorporating additional items to differentiate DLB from VCI. Clinical data were collected from a dementia registry in Taiwan, including patients with AD, VCI, and DLB. The diagnostic accuracy of DLBCSQ versions was evaluated using receiver operating characteristic (ROC) analyses across subgroups, including mild cognitive impairment with Lewy bodies (LB-MCI).ResultsBoth DLBCSQ and DLBCSQ11 demonstrated strong discriminatory ability, with area under the curve (AUC) values exceeding 0.84 for differentiating DLB from non-DLB syndromes. DLBCSQ11 showed greater specificity for distinguishing DLB from VCI, though about 20% of VCI patients still exhibited DLB-like features. Supplementary questions on visual hallucinations and tremors further improved detection of prodromal or mixed DLB cases.ConclusionsThe DLBCSQ9 and DLBCSQ11 represent practical and effective tools for clinical and bedside identification of DLB. By improving early recognition and differentiation from AD and VCI, these instruments may facilitate timely diagnosis, guide treatment decisions, and support future research on mixed dementia syndromes.},
}

@article {pmid41984500,
year = {2026},
author = {Shah, S and Tran, T and Wadhwa, SS and Huerta, GI and Ovalle-Eliseo, S and Martinez, A and Vossel, K and Campos, B and Bholat, M and Moreno, G and Diaz-Santos, M and Chang, TS},
title = {Increased dementia diagnosis and workup in primary care with a bilingual screening tool integrated in the electronic health record.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441776},
doi = {10.1177/13872877261441776},
pmid = {41984500},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) affects over 10% of adults aged 65 and older. Black and Hispanic/Latino individuals experience 1.5-2.0 times higher prevalence than White individuals, yet AD remains underdiagnosed, particularly in non-White populations. Common screening tools such as the Mini-Mental State Examination and Montreal Cognitive Assessment are limited by time burden and cultural sensitivity.ObjectiveTo evaluate the impact of integrating a brief dementia screening tool (DST) into the electronic health record (EHR) on diagnosis, evaluation, and treatment in primary care.MethodsThe DST, developed by the University of California Alzheimer's Disease Centers and the California Department of Public Health, takes under five minutes and includes a three-question patient form, optional informant questionnaire, and Mini-Cog. It was translated and culturally adapted for Spanish-speaking patients and embedded in the EHR. Patients aged ≥60 in a diverse Los Angeles County family medicine clinic completed the DST before annual wellness visits. We conducted a pre-post study comparing patients without prior dementia diagnoses during pre-intervention (February 2021-August 2022) and post-intervention (January 2023-June 2024) periods. Primary outcome was new dementia diagnosis; secondary outcomes included medications, referrals, labs, and imaging.ResultsAmong 1515 eligible patients post-intervention, 1249 completed screening. New dementia diagnoses increased from 0.75% pre-DST to 2.45% among those screening positive (adjusted OR 2.99; p = 0.01). Dementia medications, laboratory orders, and specialty referrals significantly increased; imaging did not.ConclusionsA brief, culturally adapted DST integrated into primary care improved dementia diagnosis, evaluation, and treatment.},
}

@article {pmid41984564,
year = {2026},
author = {Shavlovskaya, OA},
title = {[The effectiveness of citicoline in the treatment of cognitive disorders].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {3},
pages = {136-140},
doi = {10.17116/jnevro2026126031136},
pmid = {41984564},
issn = {1997-7298},
mesh = {Humans ; *Cytidine Diphosphate Choline/therapeutic use ; *Nootropic Agents/therapeutic use ; Parkinson Disease/drug therapy/complications ; *Cognitive Dysfunction/drug therapy ; Alzheimer Disease/drug therapy ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Stroke/complications ; },
abstract = {Randomized controlled trials, systematic reviews, and meta-analyses have shown that citicoline is highly effective in the treatment of vascular cognitive impairments (CI) of various origins (post-stroke, chronic cerebral ischemia (CCI)), post-traumatic CI, mild CI in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), and in patients with age-related memory impairments. Citicoline administration regimens: 1) post-stroke CI at a dose of 1000 mg/day. for a course of 4-12 months; 2) mild CI of vascular origin at a dose of 500 mg/day for a course of 3-9 months; 3) CI against the background of CCI at a dose of 500-2000 mg, the duration of the course depends on the severity of the symptoms; 4) non-demented CI at a dose of 1000 mg/day course of 9 months; 5) mild CI against Parkinson's disease at a dose of 1000 mg/day 12-18 months.},
}

Humans
*Cytidine Diphosphate Choline/therapeutic use
*Nootropic Agents/therapeutic use
Parkinson Disease/drug therapy/complications
*Cognitive Dysfunction/drug therapy
Alzheimer Disease/drug therapy
Randomized Controlled Trials as Topic
Treatment Outcome
Stroke/complications

@article {pmid41985059,
year = {2026},
author = {Du, JH and Shen, M and Mathys, H and Roeder, K},
title = {Uncovering causal relationships in single-cell omic studies with causarray.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {2},
pages = {},
doi = {10.1093/bib/bbag175},
pmid = {41985059},
issn = {1477-4054},
mesh = {*Single-Cell Analysis/methods ; Humans ; Animals ; Mice ; Alzheimer Disease/genetics ; *Genomics/methods ; Brain/metabolism ; Autistic Disorder/genetics ; Machine Learning ; Transcriptome ; Case-Control Studies ; },
abstract = {Advances in single-cell sequencing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technologies have enabled detailed case-control comparisons and experimental perturbations at single-cell resolution. However, uncovering causal relationships in observational genomic data remains challenging due to selection bias and inadequate adjustment for unmeasured confounders, particularly in heterogeneous datasets. To address these challenges, we introduce causarray, a robust causal inference framework for analyzing array-based genomic data at both pseudo-bulk and single-cell levels under unmeasured confounding. causarray integrates a generalized confounder adjustment method to account for unmeasured confounders and employs semiparametric inference with flexible machine learning techniques to ensure robust statistical estimation of treatment effects. Benchmarking results show that causarray robustly separates treatment effects from confounders while preserving biological signals across diverse settings. We also apply causarray to two single-cell genomic studies: (i) an in vivo Perturb-seq study of autism risk genes in developing mouse brains and (ii) a case-control study of Alzheimer's disease (AD) using three human brain transcriptomic datasets. In these applications, causarray identifies clustered causal effects of multiple autism risk genes and consistent causally affected genes across AD datasets, uncovering biologically relevant pathways directly linked to neuronal development and synaptic functions that are critical for understanding disease pathology.},
}

*Single-Cell Analysis/methods
Humans
Animals
Mice
Alzheimer Disease/genetics
*Genomics/methods
Brain/metabolism
Autistic Disorder/genetics
Machine Learning
Transcriptome
Case-Control Studies

@article {pmid41973126,
year = {2026},
author = {Shinde, P and Sathiyanarayanan, A and Lohidasan, S},
title = {Exploration of potential neuroprotective agents from medicinal plants for the treatment of Alzheimer's disease-approach through in silico ADMET, network pharmacology, docking, and dynamics studies.},
journal = {Journal of molecular modeling},
volume = {32},
number = {5},
pages = {},
pmid = {41973126},
issn = {0948-5023},
mesh = {*Alzheimer Disease/drug therapy ; *Molecular Docking Simulation ; *Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Molecular Dynamics Simulation ; Network Pharmacology ; Humans ; *Plants, Medicinal/chemistry ; *Phytochemicals/chemistry/pharmacology/pharmacokinetics ; },
abstract = {CONTEXT: A degenerative brain disorder that causes memory loss is Alzheimer's disease (AD). Phytoconstituents represent a promising therapeutic strategy due to their diverse bioactivities and favourable safety profiles. This study aimed to identify potential neuroprotective phytoconstituents for AD by pharmacokinetic screening, network pharmacology, molecular docking and molecular dynamics simulation. Among 22 phytoconstituents analysed, the network revealed GSK3β, STAT3, MAOB, ESR1, and PTGS2 as key AD-associated targets. Docking results were supported by dynamic stability analysis. The combined computational results support rosmariquinone as a potential neuroprotective lead compound for AD treatment.

METHODS: Pharmacokinetic and toxicity profiling of 22 phytoconstituents was performed using Swiss ADME and ProTox III software. Target prediction and construction of the phytoconstituent-disease target-gene interaction network were conducted using Swiss Target Prediction, Gene Card and Cytoscape. Pathway enrichment was evaluated via KEGG and GO analysis. Molecular docking of all shortlisted phytoconstituents against AD-related targets was carried out using AutoDock Vina, while 500 ns molecular dynamics simulations were performed using the Desmond module of the Schrödinger Suite to assess complex stability, RMSD, RMSF and hydrogen-bond fluctuation.},
}

*Alzheimer Disease/drug therapy
*Molecular Docking Simulation
*Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use
Molecular Dynamics Simulation
Network Pharmacology
Humans
*Plants, Medicinal/chemistry
*Phytochemicals/chemistry/pharmacology/pharmacokinetics

@article {pmid41973520,
year = {2026},
author = {Franco Rocha, OY and Janelsins, MC and Magnuson, A},
title = {Decision-making and treatment planning for older adults with pre-existing cognitive impairment and cancer.},
journal = {Current opinion in supportive and palliative care},
volume = {},
number = {},
pages = {},
doi = {10.1097/SPC.0000000000000804},
pmid = {41973520},
issn = {1751-4266},
abstract = {PURPOSE OF REVIEW: The review aims to synthesize the current evidence on decision-making and cancer treatment planning for older adults with pre-existing cognitive impairment, Alzheimer's disease, and other related dementias.

RECENT FINDINGS: Current decision-making practices are not standardized, and evidence suggests that oncology physicians conduct burden-benefit analyses to guide treatment planning. There was a consensus on the importance of involving caregivers into the decision-making process. However, caregivers experience feelings of anxiety, uncertainty, and extra burden when deciding between treatment options and providing care. Nursing home staffs were frequently excluded from the decision-making process and were perceived as unprepared to identify and manage cancer symptoms. The planning and provision of care for this population can be guided by a comprehensive geriatric assessment (CGA). CGA can inform the decision-making process based on the patient's functionality and caregiver's resources, facilitate management of cancer care, guide the identification and management of cancer symptoms, and assist communication with patients and their caregivers.

SUMMARY: Decision-making and treatment planning for older adults with cancer and pre-existing cognitive impairment lacks standardization. CGA offers a standardized approach to guide treatment decisions, manage symptoms, and coordinate care by highlighting the needs and resources of patients and caregivers.},
}

@article {pmid41974642,
year = {2026},
author = {Xing, L and Liu, A and Gao, W and Li, J and Yao, M and Song, J and Duan, P and Li, H},
title = {Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71330},
doi = {10.1002/alz.71330},
pmid = {41974642},
issn = {1552-5279},
support = {82105035//National Natural Science Foundation of China/ ; LH2023H064//Nature Science Foundation of Heilongjiang Province/ ; ZHY2024-304//Research Project of the Traditional Chinese Medicine Administration of Heilongjiang Province/ ; },
mesh = {Humans ; *Exosomes/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; *Mitochondria/metabolism ; *Neurons/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.},
}

Humans
*Exosomes/metabolism
*Alzheimer Disease/metabolism/therapy/pathology
*Mitochondria/metabolism
*Neurons/metabolism
Animals
Autophagy/physiology

@article {pmid41975594,
year = {2026},
author = {Xu, L and Cheng, G and Hu, F and Duan, T and Han, M and Meng, H and Sun, Y and Zeng, D and Zheng, W and Yang, X and Wang, X and Tan, W and Zeng, Y},
title = {Molecular subtypes of the Alzheimer's disease spectrum: Multimodal biomarker integration, mechanistic validation, and adaptive clinical translation.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00911},
pmid = {41975594},
issn = {1673-5374},
abstract = {Alzheimer's disease exhibits considerable heterogeneity in its clinical progression, neuropathological features, and underlying etiological mechanisms. However, current clinical diagnosis and treatment primarily rely on positron emission tomography and evidence-based cerebrospinal fluid biomarkers, with less emphasis on molecular subtypes, thereby limiting meaningful subtype stratification and personalized therapeutic interventions. Given advances in large-scale multi-omics technologies, single-cell genomics, and molecular imaging, research on the molecular subtypes of Alzheimer's disease is gradually increasing. In this review, we evaluate the growing body of studies on molecular subtypes of Alzheimer's disease through a comparative analysis of multimodal biomarkers, including cerebrospinal fluid proteomic profiles, single-nucleus transcriptomic architectures, neuroimaging endophenotypes, and adaptive clinical translation. We also analyze phenotypic variations across the Alzheimer's disease continuum to bridge molecular discoveries with clinical manifestations. Findings include proteomics-driven investigations that have identified five distinct cerebrospinal fluid proteomic subtypes. These subtypes are associated with divergent genetic backgrounds, survival rates, and cortical atrophy patterns, and are mechanistically linked to aberrant neuronal hyperproliferation, dysregulated innate immune activation, abnormalities in RNA splicing and processing, choroid plexus dysfunction, and blood-brain barrier impairment. Parallel progress in single-cell technologies, such as single-nucleus RNA sequencing, single-cell ATAC sequencing, and single-cell RNA sequencing applied to postmortem brain tissues, has enabled precise mapping of pathological cellular states across various brain regions. These approaches have revealed that molecular alterations in Alzheimer's disease exhibit high cell-type specificity and have uncovered novel disease-associated vascular-glial-neuronal co-expression modules, as well as vasculature-specific mechanisms correlated with APOE4 genetic risk. Tau- positron emission tomography neuroimaging studies have delineated four distinct spatiotemporal trajectories of tau accumulation, including temporo-lateral, occipital, hippocampal-sparing, and limbic subtypes, each associated with unique clinical phenotypes. From a genetic perspective, large-scale genome-wide association studies have identified approximately 75 risk loci implicated in Alzheimer's disease pathogenesis, including 42 previously unreported genomic regions, highlighting biological processes such as microglial activation, lipid metabolism, and synaptic function. Multi-omics analyses have further defined three hierarchical subtypes of Alzheimer's disease, which are primarily distinguished by dysregulation in either metabolic pathways, astroglial activation, or vascular and leptomeningeal function. Despite these advances in delineating heterogeneity, the field continues to face significant challenges. Key among these are the lack of cross-cohort reproducibility, standardized subtyping criteria, and evidence-based clinical validation.},
}

@article {pmid41975601,
year = {2026},
author = {Wei, L and Ren, H and Lin, Y and Sun, J and Nie, S and Gao, X and Huang, Y},
title = {Cultivation and transplantation of engineered stem cells: A new strategy for promoting repair of central nervous system injury.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01121},
pmid = {41975601},
issn = {1673-5374},
abstract = {Due to the complex pathological microenvironment of nerve injury, the ability for self-repair is extremely limited, posing a major challenge for clinical treatment. Stem cell therapy has brought hope for nerve regeneration; however, natural stem cells have limitations such as low survival rates, poor directional differentiation efficiency, and insufficient secretion of neurotrophic factors. In recent years, the development of engineered stem cells through gene editing, biomaterial co-culture, or pretreatment has emerged as a promising new strategy. This review systematically describes the current application status of engineered stem cells in the repair of nerve injury. It summarizes the pathological mechanisms of nerve injury and the biological processes of endogenous neurogenesis and regeneration, providing a theoretical basis for engineering interventions. It details the engineering strategies used, including engineering methods, cell sources, cell processing technologies, cell delivery vehicles, and cell function regulation. Additionally, it discusses the multiple mechanisms of engineered stem cells, highlighting that their therapeutic effect is not solely dependent on differentiation into neurons or glial cells for replacement. Instead, their therapeutic effects primarily arise from the strong paracrine effects of engineered stem cells: they secrete neurotrophic factors to support the survival of host neurons, regulate the immune microenvironment, release exosomes to deliver repair-related miRNA or proteins, and promote angiogenesis and axon myelination, thereby facilitating the reconstruction of neural circuits. This review provides insights into the application of engineered stem cells in preclinical research, highlighting significant functional improvements in various neurological disease models such as spinal cord injury, stroke, Alzheimer's disease, and Parkinson's disease. Finally, this paper discusses the key challenges facing the clinical translation of this technology, including the risks of tumorigenicity, the long-term survival and safety of transplanted cells, the need for standardized preparation processes, and ethical and regulatory considerations. In summary, engineered stem cells demonstrate therapeutic potential beyond that of natural stem cells through synergistic multi-mechanism effects, providing more precise and efficient strategies for nerve injury repair. This review not only outlines the technological systems and theoretical advancements in this field but also establishes an important academic foundation for promoting the transition from basic research to clinical application. It systematically summarizes the mechanisms and applications of engineered stem cells in neural repair, emphasizing their potential and existing bottlenecks in translational medicine, thus providing a theoretical basis and directional guidance for future research.},
}

@article {pmid41975605,
year = {2026},
author = {Luo, L and Yan, T and Liu, W and Gao, Y and Tang, X and Yang, L and Zhao, M},
title = {Homoplantaginin regulates various pharmacological pathways: Candidate drugs for multi-target relief of cognitive decline and pathological changes in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00660},
pmid = {41975605},
issn = {1673-5374},
abstract = {Alzheimer's disease is an age-associated neurodegenerative disorder with a complex pathogenesis. As a result, multi-target drug strategies have emerged in the development of anti- Alzheimer's disease medications. Natural compounds exhibit various pharmacological effects and low toxicity, making them beneficial for multifaceted intervention. Considering that NOD-like receptor protein 3 inflammasome-mediated inflammation is crucial for the treatment of Alzheimer's disease, we identified natural NOD-like receptor protein 3 inhibitors using molecular docking and a lipopolysaccharide/adenosine triphosphate-induced J774A.1 cell inflammation model. We found that homoplantaginin stably bound to NOD-like receptor protein 3, and surface plasmon resonance experiments further demonstrated that its binding affinity was 86.30 μM. Moreover, homoplantaginin effectively inhibited inflammation mediated by NOD-like receptor protein 3 inflammasome activation in J774A.1 cells by reducing the levels of interleukin-1β, interleukin-18, mature interleukin-1β (p17), and active caspase-1 (p20). Additionally, homoplantaginin treatment inhibited apoptosis and oxidative damage in L-glutamate-induced PC12 cells, as well as in aluminum chloride and D-galactose-induced Alzheimer's disease mice. The effects of homoplantaginin on Alzheimer's disease-like behavioral impairments were evaluated using the open field test, Y-maze, and Morris water maze. Results showed that there was no effect on control mice after administration of homoplantaginin once daily for 30 consecutive days, while locomotor and cognitive impairments in Alzheimer's disease mice were significantly alleviated, exhibiting superior efficacy compared with the positive drug donepezil. Importantly, consistent with the observations in J774A.1 cells, homoplantaginin inhibited the activation of the NOD-like receptor protein 3 inflammasome in the serum and brain tissues of Alzheimer's disease mice. NOD-like receptor protein 3 knockout hindered the improvement effect of homoplantaginin on cognitive deficits in Alzheimer's disease zebrafish induced by AlCl3 and D-gal, indicating that homoplantaginin enhances cognitive function by inhibiting activation of NOD-like receptor protein 3. Furthermore, homoplantaginin treatment reduced amyloid-beta deposition, oxidative stress, and apoptosis in Alzheimer's disease mice. Notably, aging is a major risk factor for Alzheimer's disease, and homoplantaginin prevented cellular senescence by regulating related biomarker levels in Alzheimer's disease mice. These results demonstrate that homoplantaginin may serve as a promising multifunctional candidate for the treatment of Alzheimer's disease.},
}

@article {pmid41975609,
year = {2026},
author = {Cao, K and Xie, J and Liang, X and Li, Y and Gong, H and Luo, H},
title = {Dendritic mesoporous silica nanoparticle-based nasal delivery carriers for passive immunotherapy of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00917},
pmid = {41975609},
issn = {1673-5374},
abstract = {Hyperphosphorylation of tau is a key pathological hallmark of Alzheimer's disease and is closely associated with cognitive impairment. Passive immunotherapy targeting hyperphosphorylated tau is a promising approach to inhibit tau pathology. However, the blood-brain barrier restricts antibodies from reaching the central nervous system and exerting their therapeutic effects. Here, we developed an intranasal biomacromolecule delivery strategy for the treatment of Alzheimer's disease using dendritic mesoporous silica nanoparticles modified with hyaluronic acid as a drug carrier. Ten-month-old C57BL/6J mice, htau mice, and 5×FAD mice were intranasally administered 100 μg of hyaluronic acid-dendritic mesoporous silica nanoparticles@4B1 (antibody dose), and brain tissues were collected to evaluate antibody delivery efficiency. Using this delivery system, the anti-p-tau396,404 antibody 4B1 was efficiently delivered to the brains of 5×FAD mice, with an enrichment of 7.31% ± 0.18% ID/g. Entry of the 4B1 antibody into the brain ameliorated tauopathy in Alzheimer's disease model mice, reduced neuronal loss and neuroinflammation caused by tau pathology, and reversed cognitive dysfunction. These findings suggest that the nasal delivery strategy based on hyaluronic acid-responsive release is an effective method for delivering antibody biomacromolecules to the central nervous system, showing high efficiency of antibody entry into brain tissue and intracellular delivery. Our findings also demonstrate the role of p-tau396,404 in passive immunotherapy for Alzheimer's disease, suggesting that immunotherapy targeting p-tau396,404 is a promising strategy for ameliorating Alzheimer's disease pathology, inhibiting the aggregation of hyperphosphorylated tau, and alleviating neurological damage and cognitive dysfunction.},
}

@article {pmid41975618,
year = {2026},
author = {Chen, S and Li, J and Zhou, J and Xie, W and Li, H and Yang, L and Chen, G and Long, C},
title = {NeuroD1 gene therapy converts reactive astrocytes to functional new neurons in a mouse model of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00721},
pmid = {41975618},
issn = {1673-5374},
abstract = {Alzheimer's disease is characterized by the presence of amyloid-beta plaques, neurofibrillary tangles, and chronic neuroinflammation. Effective therapies capable of restoring neuronal loss, a key pathological feature of Alzheimer's disease are lacking. Our previous studies have demonstrated that overexpression of neuronal differentiation 1 (NeuroD1) in astrocytes can convert astrocytes into neurons in Alzheimer's disease models and this astrocyte-to-neuron conversion technology can rescue pathological features in models of stroke and epilepsy. This study investigated whether NeuroD1-mediated in vivo reprogramming of reactive astrocytes into functional neurons could rescue neurodegeneration and cognitive decline in amyloid precursor protein/presenilin 1 transgenic Alzheimer's disease model mice. Using retro-orbital delivery of AAV-PHP.eB-GFAP-NeuroD1-GFP, we achieved broad astrocyte-to-neuron conversion throughout the brain of 7-month-old Alzheimer's disease mice. Three months post-treatment, immunostaining revealed significant neuronal regeneration in the cortex and hippocampus, accompanied by a marked reduction in neuroinflammatory markers. The converted neurons exhibited mature electrophysiological properties, including action potentials and synaptic activity, which correlated with increased neuronal density in the hippocampus. Morris water maze test demonstrated that NeuroD1-treated mice exhibited restored spatial learning and memory compared with control animals. These findings demonstrate that NeuroD1-driven neuroregeneration via gene therapy not only replenishes neuronal populations but also reduces key pathological features related to Alzheimer's disease, including neuroinflammation and amyloid plaque burden, ultimately reducing cognitive impairment. Our findings highlight in vivo astrocyte-to-neuron reprogramming through systemic astrocyte-to-neuron delivery as a promising and transformative strategy for treating Alzheimer's disease and related neurodegenerative disorders.},
}

@article {pmid41977320,
year = {2026},
author = {Toledano-Pinedo, M and Porro-Pérez, A and Schäker-Hübner, L and Diez-Iriepa, D and Iriepa, I and Siwek, A and Wolak, M and Satała, G and Bojarski, AJ and Doroz-Płonka, A and Handzlik, J and Godyń, J and Dallemagne, P and Rochais, C and Davis, A and Since, M and Pérez, B and Bellver-Sanchis, A and Irisarri, A and Pallàs, M and Solana-Manrique, C and López-Muñoz, F and Ismaili, L and Griñán-Ferré, C and Paricio, N and K Hansen, F and Więckowska, A and Marco-Contelles, J},
title = {Polyfunctionalized N-Arylsulfonyl Indoles: Identification of (E)-N-Hydroxy-3-{3-[(5-(3-(piperidin-1-yl)propoxy]-1H-indol-1-yl)sulfonyl]phenyl}a
crylamide (MTP150) for the Epigenetic-Based Therapy of Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073135},
pmid = {41977320},
issn = {1422-0067},
support = {PID2019-105813RB-C21//AEI (Government of Spain/ ; },
mesh = {Animals ; *Parkinson Disease/drug therapy/genetics/metabolism ; *Indoles/pharmacology/chemistry/therapeutic use ; Disease Models, Animal ; Caenorhabditis elegans/drug effects/genetics ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Epigenesis, Genetic/drug effects ; Oxidative Stress/drug effects ; *Acrylamides/pharmacology/chemistry ; },
abstract = {Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.},
}

Animals
*Parkinson Disease/drug therapy/genetics/metabolism
*Indoles/pharmacology/chemistry/therapeutic use
Disease Models, Animal
Caenorhabditis elegans/drug effects/genetics
Humans
*Neuroprotective Agents/pharmacology/chemistry
*Epigenesis, Genetic/drug effects
Oxidative Stress/drug effects
*Acrylamides/pharmacology/chemistry

@article {pmid41977439,
year = {2026},
author = {Bougea, A},
title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073260},
pmid = {41977439},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; *RNA, Untranslated/genetics ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics ; Genetic Therapy/methods ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.},
}

Humans
*Neurodegenerative Diseases/genetics/therapy
Animals
*RNA, Untranslated/genetics
MicroRNAs/genetics
RNA, Long Noncoding/genetics
Genetic Therapy/methods

@article {pmid41977460,
year = {2026},
author = {Taboada-Jara, T and Ribalta, M and Romero-Becerra, F and Muixí, J and Bellver-Sanchis, A and Griñán-Ferré, C and Escolano, C and Pallàs, M},
title = {Usefulness of C. elegans Models of Alzheimer's and Huntington's Disease to Evaluate Novel Imidazoline I2 Receptor Ligands.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073282},
pmid = {41977460},
issn = {1422-0067},
support = {PDC2022-133441-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00357//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PID2022-138079OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; N° 19/2015//Ministerio de Economía y Finanzas and Programa Nacional de Becas "Don Carlos Antonio López"/ ; //Càtedra UB Dr. Antoni Esteve i Subirana de Recerca en Farmacologia/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Huntington Disease/metabolism/drug therapy/genetics ; Disease Models, Animal ; *Imidazoline Receptors/metabolism ; Ligands ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Oxidative Stress/drug effects ; Humans ; Animals, Genetically Modified ; Caenorhabditis elegans Proteins/metabolism/genetics ; Amyloid beta-Peptides/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's (AD) and Huntington's (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
*Huntington Disease/metabolism/drug therapy/genetics
Disease Models, Animal
*Imidazoline Receptors/metabolism
Ligands
*Alzheimer Disease/metabolism/drug therapy/genetics
Oxidative Stress/drug effects
Humans
Animals, Genetically Modified
Caenorhabditis elegans Proteins/metabolism/genetics
Amyloid beta-Peptides/metabolism/genetics
*Neuroprotective Agents/pharmacology

@article {pmid41977473,
year = {2026},
author = {Bivona, G and Ghersi, G},
title = {Microglia-Astrocyte Cooperation and Peripheral T Cells in Alzheimer's Disease: State-of-the-Art and Treatment Perspectives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073295},
pmid = {41977473},
issn = {1422-0067},
mesh = {*Alzheimer Disease/immunology/therapy/pathology/metabolism ; Humans ; *Microglia/metabolism/pathology/immunology ; *T-Lymphocytes/immunology/metabolism ; *Astrocytes/metabolism/pathology/immunology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells.},
}

*Alzheimer Disease/immunology/therapy/pathology/metabolism
Humans
*Microglia/metabolism/pathology/immunology
*T-Lymphocytes/immunology/metabolism
*Astrocytes/metabolism/pathology/immunology
Animals
Amyloid beta-Peptides/metabolism